ID: h-var-9c0368bb70
Hypothesis
Hippocampal CA3-CA1 synaptic rescue via DHHC2-mediated PSD95 palmitoylation stabilization
The hypothesis proposes that stabilizing hippocampal CA3-CA1 synaptic function through DHHC2-mediated PSD95 palmitoylation can rescue synaptic transmission in Alzheimer's disease (AD), with BDNF signaling as a key downstream effector of .
neuroscience
🔴 Alzheimer's Disease🔮 Lysosomal / Autophagy🔬 Microglial Biology🧠 Neurodegeneration🔥 Neuroinflammation
EvidencePending (0%)📖 11 cit🗣 3 debates✓ 53 support✗ 19 oppose
⚠ Low Validation Senate Quality Gates →
🧪 Overview
Mechanistic Overview
The hypothesis proposes that stabilizing hippocampal CA3-CA1 synaptic function through DHHC2-mediated PSD95 palmitoylation can rescue synaptic transmission in Alzheimer's disease (AD), with BDNF signaling as a key downstream effector of this structural stabilization.
Molecular Mechanism and Rationale
DHHC2 palmitoyltransferase catalyzes reversible palmitoylation of PSD95 at cysteine residues 3 and 5, promoting membrane association and preventing degradation by the ubiquitin-proteasome system. In AD, amyloid-β oligomers disrupt this process by sequestering Rab8a, a small GTPase required for DHHC2 membrane trafficking and localization to postsynaptic sites. This disruption leads to hypopalmitoylation of PSD95, causing its dissociation from the postsynaptic membrane and subsequent proteasomal degradation, which destabilizes AMPA and NMDA receptor clustering and impairs synaptic transmission. BDNF signaling becomes compromised downstream as PSD95 loss disrupts TrkB receptor complex assembly and associated signaling cascades essential for synaptic plasticity and neuronal survival [1].
Gene Expression Context
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🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
graph TD
A["Amyloid-beta<br/>Oligomers"] -->|"Sequestration"| B["Rab8a Small<br/>GTPase"]
B -->|"Impaired trafficking"| C["DHHC2<br/>Palmitoyltransferase"]
C -->|"Reduced membrane<br/>localization"| D["PSD95<br/>Hypopalmitoylation"]
E["Normal DHHC2<br/>Activity"] -->|"Palmitoylation at<br/>Cys3 and Cys5"| F["PSD95 Membrane<br/>Association"]
F -->|"Scaffold stability"| G["AMPA Receptor<br/>Clustering"]
F -->|"Scaffold stability"| H["NMDA Receptor<br/>Clustering"]
D -->|"Loss of membrane<br/>association"| I["PSD95 Dissociation<br/>from Membrane"]
I -->|"Targeting for<br/>degradation"| J["Ubiquitin-Proteasome<br/>System Activation"]
J -->|"Protein degradation"| K["PSD95 Loss"]
K -->|"Disrupted receptor<br/>clustering"| L["Synaptic Transmission<br/>Impairment"]
K -->|"Loss of scaffold<br/>integrity"| M["TrkB Receptor<br/>Complex Disruption"]
M -->|"Impaired signaling"| N["BDNF Pathway<br/>Dysfunction"]
N -->|"Reduced neurotrophic<br/>support"| O["Synaptic Plasticity<br/>Deficits"]
O -->|"Functional decline"| P["CA3-CA1 Synaptic<br/>Failure"]
P -->|"Circuit dysfunction"| Q["Hippocampal Memory<br/>Impairment"]
L -->|"Excitotoxicity"| R["Neuronal Survival<br/>Compromise"]
classDef normal fill:#4fc3f7,stroke:#2196f3,color:#0d0d1a
classDef therapeutic fill:#81c784,stroke:#4caf50,color:#0d0d1a
classDef pathology fill:#ef5350,stroke:#f44336,color:#0d0d1a
classDef outcome fill:#ffd54f,stroke:#ff9800,color:#0d0d1a
classDef molecular fill:#ce93d8,stroke:#9c27b0,color:#0d0d1a
class E,F,C normal
class A,D,I,J,K pathology
class N,O,P,Q,R outcome
class B,G,H,L,M molecular⚖️ Evidence
⚖️ Evidence Matrix53 supports19 contradicts
Supports
Adult hippocampal neurogenesis is impaired in AD
Abstract
Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain. Recent evidence suggests that adult hippocampal neurogenesis (AHN) persists throughout life in mammals, including humans. These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory. Importantly, studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases. Alzheimer's disease (AD) is one of the most common forms of dementia affecting millions of people. Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus. Therefore, there has been growing interest in identifying how hippocampal neurogenesis is affected in AD. However, the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood. In this review, we summarized the recent literature
Supports
Hippocampal circuit mapping reveals CA3-CA1 dysfunction in AD models
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts in countries with aging populations. Existing therapeutic approaches that have been based on neurochemical and neuropathological findings are largely ineffective. This lack of progress suggests we require a new framework for future AD therapies. The examination of neural circuit mechanisms in AD mouse models is an emerging focus for identifying new AD treatment strategies. We now know there are neural circuit-level maladaptive alterations in AD brains, some of which appear very early in the disease process before neuropathological features are detectable. Recent advancements in viral-genetic technologies allow us to quantitatively map the cell-type-specific neural circuit connections in AD mouse models. Monosynaptic rabies virus mapping reveals age-progressive changes in both long-range and local hippocampal neural circuit connectivity in AD mouse models - and provides explanations fo
Supports
Visual circuit activation via glymphatic modulation improves memory
Abstract
Alzheimer's disease is characterized by progressive amyloid deposition and cognitive decline, yet the pathological mechanisms and treatments remain elusive. Here we report the therapeutic potential of low-intensity 40 hertz blue light exposure in a 5xFAD mouse model of Alzheimer's disease. Our findings reveal that light treatment prevents memory decline in 4-month-old 5xFAD mice and motivation loss in 14-month-old 5xFAD mice, accompanied by restoration of glial water channel aquaporin-4 polarity, improved brain drainage efficiency, and a reduction in hippocampal lipid accumulation. We further demonstrate the beneficial effects of 40 hertz blue light are mediated through the activation of the vLGN/IGL-Re visual circuit. Notably, concomitant use of anti-Aβ antibody with 40 hertz blue light demonstrates improved soluble Aβ clearance and cognitive performance in 5xFAD mice. These findings offer functional evidence on the therapeutic effects of 40 hertz blue light in Aβ-related pathologies
Supports
Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression.
Abstract
Background: Depression is a mental disorder that poses a serious threat to human health. Adult hippocampal neurogenesis (AHN) is closely associated with the efficacy of antidepressants. Chronic treatment with corticosterone (CORT), a well-validated pharmacological stressor, induces depressive-like behaviors and suppresses AHN in experimental animals. However, the possible mechanisms of chronic CORT action remain elusive. Methods: A chronic CORT treatment (0.1 mg/mL, drinking water for 4 weeks) was applied to prepare a mouse model of depression. Immunofluorescence was performed to analyze the hippocampal neurogenesis lineage, and immunoblotting, immunofluorescence, electron microscopy, and adeno-associated virus (AAV) expressing a pH-sensitive tandemly tagged light chain 3 (LC3) protein were used to analyze neuronal autophagy. AAV-hSyn-miR30-shRNA was used to knock down autophagy-related gene 5 (Atg5) expression in the neurons. Results: Chronic CORT induces depressive-like behaviors and
Supports
Astrocytes and brain-derived neurotrophic factor (BDNF).
Abstract
Astrocytes are emerging in the neuroscience field as crucial modulators of brain functions, from the molecular control of synaptic plasticity to orchestrating brain-wide circuit activity for cognitive processes. The cellular pathways through which astrocytes modulate neuronal activity and plasticity are quite diverse. In this review, we focus on neurotrophic pathways, mostly those mediated by brain-derived neurotrophic factor (BDNF). Neurotrophins are a well-known family of trophic factors with pleiotropic functions in neuronal survival, maturation and activity. Within the brain, BDNF is the most abundantly expressed and most studied of all neurotrophins. While we have detailed knowledge of the effect of BDNF on neurons, much less is known about its physiology on astroglia. However, over the last years new findings emerged demonstrating that astrocytes take an active part into BDNF physiology. In this work, we discuss the state-of-the-art knowledge about astrocytes and BDNF. Indeed, as
Supports
Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice.
Abstract
Aging is one of the main risk factors for cognitive dysfunction. During aging process, the decrease of brain-derived neurotrophic factor (BDNF) and the impairment of astrocyte function contribute to the cognitive impairment. Metrnl, a neurotrophic factor, promotes neural growth, migration and survival, and supports neural function. In this study, we investigated the role of Metrnl in cognitive functions. D-galactose (D-gal)-induced aging model was used to simulate the process of aging. Cognitive impairment was assessed by the Morris water maze test. We showed that Metrnl expression levels were significantly increased in the hippocampus of D-gal-induced aging mice. Metrnl knockout did not affect the cognitive functions in the baseline state, but aggravated the cognitive impairment in the D-gal-induced aging mice. Furthermore, Metrnl knockout significantly reduced hippocampal BDNF, TrkB, and glial fibrillary acidic protein (GFAP) levels in the D-gal-induced aging mice. In the D-gal-induc
Supports
IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis.
Abstract
Adult neurogenesis in the dentate gyrus of the hippocampus is regulated by specific microglia groups and functionally implicated in behavioral responses to stress. However, the role of microglia in hippocampal neurogenesis and stress resilience remains unclear. We identified interleukin 4 (IL4)-driven microglia characterized by high expression of Arg1, which is critical in maintaining hippocampal neurogenesis and stress resistance. Decreasing Arg1+ microglia in the hippocampus by knocking down the microglial IL4R suppressed hippocampal neurogenesis and enhanced stress vulnerability. Increasing Arg1+ microglia in the hippocampus by enhancing IL4 signaling restored hippocampal neurogenesis and the resilience to stress-induced depression. Brain-derived neurotrophic factor (BDNF) was found necessary for the proneurogenesis effects of IL4-driven microglia. Together, our findings suggest that IL4-driven microglia in the hippocampus trigger BDNF-dependent neurogenesis responding to chronic st
Supports
Neuronal extracellular vesicles and associated microRNAs induce circuit connectivity downstream BDNF.
Abstract
Extracellular vesicles (EVs) have emerged as mediators of cellular communication, in part via the delivery of associated microRNAs (miRNAs), small non-coding RNAs that regulate gene expression. We show that brain-derived neurotrophic factor (BDNF) mediates the sorting of miR-132-5p, miR-218-5p, and miR-690 in neuron-derived EVs. BDNF-induced EVs in turn increase excitatory synapse formation in recipient hippocampal neurons, which is dependent on the inter-neuronal delivery of these miRNAs. Transcriptomic analysis further indicates the differential expression of developmental and synaptogenesis-related genes by BDNF-induced EVs, many of which are predicted targets of miR-132-5p, miR-218-5p, and miR-690. Furthermore, BDNF-induced EVs up-regulate synaptic vesicle (SV) clustering in a transmissible manner, thereby increasing synaptic transmission and synchronous neuronal activity. As BDNF and EV-miRNAs miR-218 and miR-132 were previously implicated in neuropsychiatric disorders such as anx
Supports
Pharmacotherapy with fluoxetine restores functional connectivity from the dentate gyrus to field CA3 in the Ts65Dn mouse model of down syndrome.
Abstract
Down syndrome (DS) is a high-incidence genetic pathology characterized by severe impairment of cognitive functions, including declarative memory. Impairment of hippocampus-dependent long-term memory in DS appears to be related to anatomo-functional alterations of the hippocampal trisynaptic circuit formed by the dentate gyrus (DG) granule cells - CA3 pyramidal neurons - CA1 pyramidal neurons. No therapies exist to improve cognitive disability in individuals with DS. In previous studies we demonstrated that pharmacotherapy with fluoxetine restores neurogenesis, granule cell number and dendritic morphology in the DG of the Ts65Dn mouse model of DS. The goal of the current study was to establish whether treatment rescues the impairment of synaptic connectivity between the DG and CA3 that characterizes the trisomic condition. Euploid and Ts65Dn mice were treated with fluoxetine during the first two postnatal weeks and examined 45-60 days after treatment cessation. Untreated Ts65Dn mice had
Supports
Functional Connectivity of Hippocampal CA3 Predicts Neurocognitive Aging via CA1-Frontal Circuit.
Abstract
The CA3 and CA1 principal cell fields of the hippocampus are vulnerable to aging, and age-related dysfunction in CA3 may be an early seed event closely linked to individual differences in memory decline. However, whether the differential vulnerability of CA3 and CA1 is associated with broader disruption in network-level functional interactions in relation to age-related memory impairment, and more specifically, whether CA3 dysconnectivity contributes to the effects of aging via CA1 network connectivity, has been difficult to test. Here, using resting-state fMRI in a group of aged rats uncontaminated by neurodegenerative disease, aged rats displayed widespread reductions in functional connectivity of CA3 and CA1 fields. Age-related memory deficits were predicted by connectivity between left CA3 and hippocampal circuitry along with connectivity between left CA1 and infralimbic prefrontal cortex. Notably, the effects of CA3 connectivity on memory performance were mediated by CA1 connectiv
Supports
Hippocampal neural circuit connectivity alterations in an Alzheimer's disease mouse model revealed by monosynaptic rabies virus tracing.
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts, particularly in countries with aging populations. The examination of neural circuit mechanisms in AD mouse models is a recent focus for identifying new AD treatment strategies. We hypothesize that age-progressive changes of both long-range and local hippocampal neural circuit connectivity occur in AD. Recent advancements in viral-genetic technologies provide new opportunities for semi-quantitative mapping of cell-type-specific neural circuit connections in AD mouse models. We applied a recently developed monosynaptic rabies tracing method to hippocampal neural circuit mapping studies in AD model mice to determine how local and global circuit connectivity to hippocampal CA1 excitatory neurons may be altered in the single APP knock-in (APP-KI) AD mouse model. To determine age-related AD progression, we measured circuit connectivity in age-matched littermate control and AD model mice at
Supports
Profiling hippocampal neuronal populations reveals unique gene expression mosaics reflective of connectivity-based degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer's disease.
Abstract
INTRODUCTION: Individuals with Down syndrome (DS) exhibit neurological deficits throughout life including the development of in Alzheimer's disease (AD) pathology and cognitive impairment. At the cellular level, dysregulation in neuronal gene expression is observed in postmortem human brain and mouse models of DS/AD. To date, RNA-sequencing (RNA-seq) analysis of hippocampal neuronal gene expression including the characterization of discrete circuit-based connectivity in DS remains a major knowledge gap. We postulate that spatially characterized hippocampal neurons display unique gene expression patterns due, in part, to dysfunction of the integrity of intrinsic circuitry. METHODS: We combined laser capture microdissection to microisolate individual neuron populations with single population RNA-seq analysis to determine gene expression analysis of CA1 and CA3 pyramidal neurons and dentate gyrus granule cells located in the hippocampus, a region critical for learning, memory, and synapti
Supports
Entorhinal-Hippocampal Circuit Integrity Is Related to Mnemonic Discrimination and Amyloid-β Pathology in Older Adults.
Abstract
Mnemonic discrimination, a cognitive process that relies on hippocampal pattern separation, is one of the first memory domains to decline in aging and preclinical Alzheimer's disease. We tested whether functional connectivity (FC) within the entorhinal-hippocampal circuit, measured with high-resolution resting state fMRI, is associated with mnemonic discrimination and amyloid-β (Aβ) pathology in a sample of 64 cognitively normal human older adults (mean age, 71.3 ± 6.4 years; 67% female). FC was measured between entorhinal-hippocampal circuit nodes with known anatomical connectivity, as well as within cortical memory networks. Aβ pathology was measured with 18F-florbetapir-PET, and neurodegeneration was assessed with subregional volume from structural MRI. Participants performed both object and spatial versions of a mnemonic discrimination task outside of the scanner and were classified into low-performing and high-performing groups on each task using a median split. Low object mnemoni
Supports
Monosynaptic Rabies Tracing Reveals Sex- and Age-Dependent Dorsal Subiculum Connectivity Alterations in an Alzheimer's Disease Mouse Model.
Abstract
The subiculum (SUB), a hippocampal formation structure, is among the earliest brain regions impacted in Alzheimer's disease (AD). Toward a better understanding of AD circuit-based mechanisms, we mapped synaptic circuit inputs to dorsal SUB using monosynaptic rabies tracing in the 5xFAD mouse model by quantitatively comparing the circuit connectivity of SUB excitatory neurons in age-matched controls and 5xFAD mice at different ages for both sexes. Input-mapped brain regions include the hippocampal subregions (CA1, CA2, CA3), medial septum and diagonal band, retrosplenial cortex, SUB, postsubiculum (postSUB), visual cortex, auditory cortex, somatosensory cortex, entorhinal cortex, thalamus, perirhinal cortex (Prh), ectorhinal cortex, and temporal association cortex. We find sex- and age-dependent changes in connectivity strengths and patterns of SUB presynaptic inputs from hippocampal subregions and other brain regions in 5xFAD mice compared with control mice. Significant sex differences
Supports
Synaptic plasticity and functional stabilization in the hippocampal formation: possible role in Alzheimer's disease.
Abstract
In this chapter we have explored the hypothesis that reactive synaptogenesis is an adaptive mechanism that can compensate for loss of a fraction of a defined neuronal population. Partial cell loss occurs during the course of aging, neurodegenerative diseases, and minor traumatic brain injuries. As cells are lost or as their function severely declines, new connections made by healthy neurons from within the population can assume parallel functions (homotypic sprouting), or fibers from converging pathways (heterotypic sprouting) can act to boost weakened signals and maintain functional stability. When cell death (or disease) progresses to the point where the pathway is broken, sprouting can no longer maintain information flow along the circuit and thus is unable to preserve function, unless new circuits can also be compensatory as, for example, after unilateral injury. We have analyzed the consequences of cell loss on the nature of circuit regrowth within the primary hippocampal circuits
Supports
Selenium and brain aging: A comprehensive review with a focus on hippocampal neurogenesis.
Abstract
Brain aging is accompanied by progressive cognitive decline and increased risk of neurodegenerative diseases, with adult hippocampal neurogenesis (AHN) playing a pivotal role in maintaining cognitive resilience. Selenium, an essential trace element, exerts significant neuroprotective and neurogenic effects predominantly through its incorporation into selenoproteins, which regulate oxidative stress, neuroinflammation, and synaptic plasticity. This review synthesizes recent advances delineating selenium's metabolism, bioavailability, and its multifaceted roles in brain development, function, and aging, emphasizing mechanisms underpinning hippocampal neurogenesis. Key molecular pathways influenced by selenium include phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Wingless/Integrated (Wnt) and brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling pathways that promote neural progenitor cell proliferation and differentiation. Selenium transport via
Supports
Genetic removal of synaptic Zn(2+) impairs cognition, alters neurotrophic signaling and induces neuronal hyperactivity.
Abstract
Vesicular Zn2+ (zinc) is released at synapses and has been demonstrated to modulate neuronal responses. However, mechanisms through which dysregulation of zinc homeostasis may potentiate neuronal dysfunction and neurodegeneration are not well-understood. We previously reported that accumulation of soluble amyloid beta oligomers (AβO) at synapses correlates with synaptic loss and that AβO localization at synapses is regulated by synaptic activity and enhanced by the release of vesicular Zn2+ in the hippocampus, a brain region that deteriorates early in Alzheimer's disease (AD). Significantly, drugs regulating zinc homeostasis inhibit AβO accumulation and improve cognition in mouse models of AD. We used both sexes of a transgenic mouse model lacking synaptic Zn2+ (ZnT3KO) that develops AD-like cognitive impairment and neurodegeneration to study the effects of disruption of Zn2+ modulation of neurotransmission in cognition, protein expression and activation, and neuronal excitability. Her
Supports
Spatiotemporal resolution of BDNF neuroprotection against glutamate excitotoxicity in cultured hippocampal neurons.
Abstract
Brain-derived neurotrophic factor (BDNF) protects hippocampal neurons from glutamate excitotoxicity as determined by analysis of chromatin condensation, through activation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3-K) signaling pathways. However, it is still unknown whether BDNF also prevents the degeneration of axons and dendrites, and the functional demise of synapses, which would be required to preserve neuronal activity. Herein, we have studied the time-dependent changes in several neurobiological markers, and the regulation of proteolytic mechanisms in cultured rat hippocampal neurons, through quantitative western blot and immunocytochemistry. Calpain activation peaked immediately after the neurodegenerative input, followed by a transient increase in ubiquitin-conjugated proteins and increased abundance of cleaved-caspase-3. Proteasome and calpain inhibition did not reproduce the protective effect of BDNF and caspase inhibition in prevent
Supports
The intra-arterial injection of microglia protects hippocampal CA1 neurons against global ischemia-induced functional deficits in rats.
Abstract
In the present study, we have attempted to elucidate the effects of the intra-arterial injection of microglia on the global ischemia-induced functional and morphological deficits of hippocampal CA1 neurons. When PKH26-labeled immortalized microglial cells, GMIR1, were injected into the subclavian artery, these exogenous microglia were found to accumulate in the hippocampus at 24 h after ischemia. In hippocampal slices prepared from medium-injected rats subjected to ischemia 48 h earlier, synaptic dysfunctions including a significant reduction of synaptic responses and a marked reduction of long-term potentiation (LTP) of the CA3-CA1 Schaffer collateral synapses were observed. At this stage, however, neither significant neuronal degeneration nor gliosis was observed in the hippocampus. At 96 h after ischemia, there was a total loss of the synaptic activity and a marked neuronal death in the CA1 subfield. In contrast, the basal synaptic transmission and LTP of the CA3-CA1 synapses were w
Supports
Human Hippocampal Neurogenesis Persists throughout Aging.
Abstract
Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal dentate gyrus (DG) region, although concurrent changes in these parameters are not well studied. Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis. It is possible that ongoing hippocampal neurogenesis sustains human-s
Supports
Dynamics of hippocampal neurogenesis in adult humans.
Abstract
Adult-born hippocampal neurons are important for cognitive plasticity in rodents. There is evidence for hippocampal neurogenesis in adult humans, although whether its extent is sufficient to have functional significance has been questioned. We have assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear-bomb-test-derived ¹⁴C in genomic DNA, and we present an integrated model of the cell turnover dynamics. We found that a large subpopulation of hippocampal neurons constituting one-third of the neurons is subject to exchange. In adult humans, 700 new neurons are added in each hippocampus per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging. We conclude that neurons are generated throughout adulthood and that the rates are comparable in middle-aged humans and mice, suggesting that adult hippocampal neurogenesis may contribute to human brain function.
Supports
The relationship between adult hippocampal neurogenesis and cognitive impairment in Alzheimer's disease.
Abstract
Neurogenesis persists throughout adulthood in the hippocampus and contributes to specific cognitive functions. In Alzheimer's disease (AD), the hippocampus is affected by pathology and functional impairment early in the disease. Human AD patients have reduced adult hippocampal neurogenesis (AHN) levels compared to age-matched healthy controls. Similarly, rodent AD models show a decrease in AHN before the onset of the classical hallmarks of AD pathology. Conversely, enhancement of AHN can protect against AD pathology and ameliorate memory deficits in both rodents and humans. Therefore, impaired AHN may be a contributing factor of AD-associated cognitive decline, rather than an effect of it. In this review we outline the regulation and function of AHN in healthy individuals, and highlight the relationship between AHN dysfunction and cognitive impairments in AD. The existence of AHN in humans and its relevance in AD patients will also be discussed, with an outlook toward future research d
Supports
Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.
Abstract
Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.
Supports
Aerobic Exercise Restores Hippocampal Neurogenesis and Cognitive Function by Decreasing Microglia Inflammasome Formation Through Irisin/NLRP3 Pathway.
Abstract
Persistent microglial inflammation is a detrimental contributor to the progression of Parkinson disease (PD) pathology and related issues such as impaired adult hippocampal neurogenesis (AHN) and cognition. We conducted a 10-week exercise program with MPTP-treated mice to determine whether neuroinflammation can be addressed by aerobic exercise and elucidate its underlying regulatory mechanisms. Ten weeks of exercise significantly reduced PD-related pathology and enhanced AHN and memory. These changes were linked to a reduction in neuronal apoptosis, microglial inflammation, and NLRP3 inflammasome activation. In cultured microglia, fibril α-synuclein reduced FNDC5/irisin protein levels and induced NLRP3 inflammasome formation and IL-1β production, which could be diminished by recombinant irisin treatment. Interestingly, "runner serum" isolated from exercising rodents enhanced FNDC5/irisin expression and reduced NLRP3 inflammasome components and IL-1β secretion in α-synuclein-treated mic
Supports
Latent toxoplasmosis impairs learning and memory yet strengthens short-term and long-term hippocampal synaptic plasticity at perforant pathway-dentate gyrus, and Schaffer collatterals-CA1 synapses.
Abstract
Investigating long-term potentiation (LTP) in disease models provides essential mechanistic insight into synaptic dysfunction and relevant behavioral changes in many neuropsychiatric and neurological diseases. Toxoplasma (T) gondii is an intracellular parasite causing bizarre changes in host's mind including losing inherent fear of life-threatening situations. We examined hippocampal-dependent behavior as well as in vivo short- and long-term synaptic plasticity (STP and LTP) in rats with latent toxoplasmosis. Rats were infected by T. gondii cysts. Existence of REP-529 genomic sequence of the parasite in the brain was detected by RT-qPCR. Four and eight weeks after infection, spatial, and inhibitory memories of rats were assessed by Morris water maze and shuttle box tests, respectively. Eight weeks after infection, STP was assessed in dentate gyrus (DG) and CA1 by double pulse stimulation of perforant pathway and Shaffer collaterals, respectively. High frequency stimulation (HFS) was ap
Supports
Deficits in synaptic function occur at medial perforant path-dentate granule cell synapses prior to Schaffer collateral-CA1 pyramidal cell synapses in the novel TgF344-Alzheimer's Disease Rat Model.
Abstract
Alzheimer's disease (AD) pathology begins decades prior to onset of clinical symptoms, and the entorhinal cortex and hippocampus are among the first and most extensively impacted brain regions. The TgF344-AD rat model, which more fully recapitulates human AD pathology in an age-dependent manner, is a next generation preclinical rodent model for understanding pathophysiological processes underlying the earliest stages of AD (Cohen et al., 2013). Whether synaptic alterations occur in hippocampus prior to reported learning and memory deficit is not known. Furthermore, it is not known if specific hippocampal synapses are differentially affected by progressing AD pathology, or if synaptic deficits begin to appear at the same age in males and females in this preclinical model. Here, we investigated the time-course of synaptic changes in basal transmission, paired-pulse ratio, as an indirect measure of presynaptic release probability, long-term potentiation (LTP), and dendritic spine density
Supports
A computational study on plasticity during theta cycles at Schaffer collateral synapses on CA1 pyramidal cells in the hippocampus.
Abstract
Cellular activity in the CA1 area of the hippocampus waxes and wanes at theta frequency (4-8 Hz) during exploratory behavior of rats. Perisomatic inhibition onto pyramidal cells tends to be strongest out of phase with pyramidal cell activity, whereas dendritic inhibition is strongest in phase with pyramidal cell activity. Synaptic plasticity also varies across the theta cycle, from strong long-term potentiation (LTP) to long-term depression (LTD), putatively corresponding to encoding and retrieval phases for information patterns encoded by pyramidal cell activity (Hasselmo et al. (2002a) Neural Comput 14:793-817). The mechanisms underpinning the phasic changes in plasticity are not clear, but it is likely that inhibition plays a role by affecting levels of electrical activity and calcium concentration at synapses. We explore the properties of synaptic plasticity during theta at Schaffer collateral synapses on CA1 pyramidal neurons and the influence of spatially and temporally targeted
Supports
Recognition Memory Induces Natural LTP-like Hippocampal Synaptic Excitation and Inhibition.
Abstract
Synaptic plasticity is a cellular process involved in learning and memory by which specific patterns of neural activity adapt the synaptic strength and efficacy of the synaptic transmission. Its induction is governed by fine tuning between excitatory/inhibitory synaptic transmission. In experimental conditions, synaptic plasticity can be artificially evoked at hippocampal CA1 pyramidal neurons by repeated stimulation of Schaffer collaterals. However, long-lasting synaptic modifications studies during memory formation in physiological conditions in freely moving animals are very scarce. Here, to study synaptic plasticity phenomena during recognition memory in the dorsal hippocampus, field postsynaptic potentials (fPSPs) evoked at the CA3-CA1 synapse were recorded in freely moving mice during object-recognition task performance. Paired pulse stimuli were applied to Schaffer collaterals at the moment that the animal explored a new or a familiar object along different phases of the test. S
Supports
Learning as a Functional State of the Brain: Studies in Wild-Type and Transgenic Animals.
Abstract
Contemporary neuroscientists are paying increasing attention to subcellular, molecular, and electrophysiological mechanisms underlying learning and memory processes. Recent studies have examined the development of transgenic mice affected at different stages of the learning process, or have emulated in animals various human pathological conditions involving cognition and motor learning. However, a parallel effort is needed to develop stimulating and recording techniques suitable for use in behaving mice in order to understand activity-dependent synaptic changes taking place during the very moment of the learning process. The in vivo models should incorporate information collected from different molecular and in vitro approaches. Long-term potentiation (LTP) has been proposed as the neural mechanism underlying synaptic plasticity, and NMDA receptors have been proposed as the molecular substrate of LTP. It now seems necessary to study the relationship of both LTP and NMDA receptors to fu
Supports
Cannabidiol and pBDNF Cotreatment Attenuates Pathological Symptoms and Improves Cognition in 3 month-Old 5XFAD Mice.
Abstract
The marginal efficiency observed with the existing therapies in Alzheimer's Disease (AD) can be attributed to the timing of the treatment. The beneficiaries of symptomatic or disease-modifying therapy for AD are mild-cognitive-impairment (MCI) or late-stage dementia patients. At this stage, the pathological features are already advanced and irreversible, as the shift in biomarker levels starts in a continuum 15-20 years prior. Early intervention, therefore, is a plausible solution to this issue. Consequently, we selected 3 month-old 5XFAD AD mice as an early intervention model. We administered cannabidiol (CBD) and plasmid brain-derived neurotrophic factor (BDNF) encapsulated in liposome nanoparticles, functionalized with penetratin and mannose for brain-targeting, as a therapy. Neuroinflammation is emerging as a key driver of AD progression by its interaction with amyloid plaques and phosphorylated tau. Therefore, CBD, which is anti-inflammatory and neuroprotective, was used. BDNF, a
Contradicts
Adult neurogenesis contribution to human cognition remains controversial
Abstract
Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain. Recent evidence suggests that adult hippocampal neurogenesis (AHN) persists throughout life in mammals, including humans. These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory. Importantly, studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases. Alzheimer's disease (AD) is one of the most common forms of dementia affecting millions of people. Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus. Therefore, there has been growing interest in identifying how hippocampal neurogenesis is affected in AD. However, the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood. In this review, we summarized the recent literature
Contradicts
BDNF delivery to CNS faces significant pharmacokinetic challenges
Abstract
BACKGROUND: Tremor is one of the most prevalent symptoms in Parkinson's Disease (PD). The progression and management of tremor in PD can be challenging, as response to dopaminergic agents might be relatively poor, particularly in patients with tremor-dominant PD compared to the akinetic/rigid subtype. In this review, we aim to highlight recent advances in the underlying pathogenesis and treatment modalities for tremor in PD. METHODS: A structured literature search through Embase was conducted using the terms "Parkinson's Disease" AND "tremor" OR "etiology" OR "management" OR "drug resistance" OR "therapy" OR "rehabilitation" OR "surgery." After initial screening, eligible articles were selected with a focus on published literature in the last 10 years. DISCUSSION: The underlying pathophysiology of tremor in PD remains complex and incompletely understood. Neurodegeneration of dopaminergic neurons in the retrorubral area, in addition to high-power neural oscillations in the cerebello-tha
Contradicts
Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment
Abstract
Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H2O
Contradicts
Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer.
Abstract
Brain-derived neurotrophic factor (BDNF) is one of the most distributed and extensively studied neurotrophins in the mammalian brain. BDNF signals through the tropomycin receptor kinase B (TrkB) and the low affinity p75 neurotrophin receptor (p75NTR). BDNF plays an important role in proper growth, development, and plasticity of glutamatergic and GABAergic synapses and through modulation of neuronal differentiation, it influences serotonergic and dopaminergic neurotransmission. BDNF acts as paracrine and autocrine factor, on both pre-synaptic and post-synaptic target sites. It is crucial in the transformation of synaptic activity into long-term synaptic memories. BDNF is considered an instructive mediator of functional and structural plasticity in the central nervous system (CNS), influencing dendritic spines and, at least in the hippocampus, the adult neurogenesis. Changes in the rate of adult neurogenesis and in spine density can influence several forms of learning and memory and can
Contradicts
Exercise therapy to prevent and treat Alzheimer's disease.
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease in the elderly with dementia, memory loss, and severe cognitive impairment that imposes high medical costs on individuals. The causes of AD include increased deposition of amyloid beta (Aβ) and phosphorylated tau, age, mitochondrial defects, increased neuroinflammation, decreased synaptic connections, and decreased nerve growth factors (NGF). While in animals moderate-intensity exercise restores hippocampal and amygdala memory through increased levels of p-AKT, p-TrkB, and p-PKC and decreased levels of Aβ, tau phosphorylation, and amyloid precursor proteins (APP) in AD. Aerobic exercise (with an intensity of 50-75% of VO2 max) prevents hippocampal volume reduction, spatial memory reduction, and learning reduction through increasing synaptic flexibility. Exercise training induces the binding of brain-derived neurotrophic factor (BDNF) to TrkB and the binding of NGF to TrkA to induce cell survival and neuronal plasticity
Contradicts
Brain-derived neurotrophic factor in Alzheimer's disease and its pharmaceutical potential.
Abstract
Synaptic abnormalities are a cardinal feature of Alzheimer's disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid β (Aβ) and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD. Although depletion of BDNF has been linked with Aβ accumulation, tau phosphorylation, neuroinflammation and neuronal apoptosis, the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown. Here, we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling. We then discu
Contradicts
Neurogenesis in the Adult and Aging Brain.
Abstract
Given that neurogenesis is regionally restricted in the adult brain, the direct contribution of changes in neurogenesis to the development of aging-related cognitive decline is likely limited, perhaps accounting for the difficulty thus far in linking the decline in neurogenesis to specific neural deficits. As investigations of the contributions of adult neurogenesis to neural function continue, however, it is reasonable to expect they will demonstrate that the aging-related loss of the plasticit
Contradicts
Age-dependent regenerative mechanisms in the brain.
Abstract
Repairing the adult mammalian brain represents one of the greatest clinical challenges in medicine. Injury to the adult brain often results in substantial loss of neural tissue and permanent functional impairment. In contrast with the adult, during development, the mammalian brain exhibits a remarkable capacity to replace lost cells. A plethora of cell-intrinsic and extrinsic factors regulate the age-dependent loss of regenerative potential in the brain. As the developmental window closes, neural stem cells undergo epigenetic changes, limiting their proliferation and differentiation capacities, whereas, changes in the brain microenvironment pose additional challenges opposing regeneration, including inflammation and gliosis. Therefore, studying the regenerative mechanisms during development and identifying what impairs them with age may provide key insights into how to stimulate regeneration in the brain. Here, we will discuss how the mammalian brain engages regenerative mechanisms upo
Contradicts
EphA4 Targeting Peptide-Conjugated Extracellular Vesicles Rejuvenates Adult Neural Stem Cells and Exerts Therapeutic Benefits in Aging Rats.
Abstract
Aging and various neurodegenerative diseases cause significant reduction in adult neurogenesis and simultaneous increase in quiescent neural stem cells (NSCs), which impact the brain's regenerative capabilities. To deal with this challenging issue, current treatments involve stem cell transplants or prevention of neurodegeneration; however, the efficacy or success of this process remains limited. Therefore, extensive and focused investigation is highly demanding to overcome this challenging task. Here, we have designed an efficient peptide-based EphA4 receptor-targeted ligand through an in silico approach. Further, this strategy involves chemical conjugation of the peptide with adipose tissue stem cell-derived EV (Exo-pep-11). Interestingly, our newly designed engineered EV, Exo-pep-11, targets NSC through EphA4 receptors, which offers promising therapeutic advantages by stimulating NSC proliferation and subsequent differentiation. Our result demonstrates that NSC successfully internal
Contradicts
Epigenetic mechanisms during ageing and neurogenesis as novel therapeutic avenues in human brain disorders.
Abstract
Ageing is the main risk factor for human neurological disorders. Among the diverse molecular pathways that govern ageing, epigenetics can guide age-associated decline in part by regulating gene expression and also through the modulation of genomic instability and high-order chromatin architecture. Epigenetic mechanisms are involved in the regulation of neural differentiation as well as in functional processes related to memory consolidation, learning or cognition during healthy lifespan. On the other side of the coin, many neurodegenerative diseases are associated with epigenetic dysregulation. The reversible nature of epigenetic factors and, especially, their role as mediators between the genome and the environment make them exciting candidates as therapeutic targets. Rather than providing a broad description of the pathways epigenetically deregulated in human neurological disorders, in this review, we have focused on the potential use of epigenetic enzymes as druggable targets to ame
Contradicts
Targeting the blood-brain barrier for the delivery of stroke therapies.
Abstract
A variety of neuroprotectants have shown promise in treating ischemic stroke, yet their delivery to the brain remains a challenge. The endothelial cells lining the blood-brain barrier (BBB) are emerging as a dynamic factor in the response to neurological injury and disease, and the endothelial-neuronal matrix coupling is fundamentally neuroprotective. In this review, we discuss approaches that target the endothelium for drug delivery both across the BBB and to the BBB as a viable strategy to facilitate neuroprotective effects, using the example of brain-derived neurotrophic factor (BDNF). We highlight the advances in cell-derived extracellular vesicles (EVs) used for CNS targeting and drug delivery. We also discuss the potential of engineered EVs as a potent strategy to deliver BDNF or other drug candidates to the ischemic brain, particularly when coupled with internal components like mitochondria that may increase cellular energetics in injured endothelial cells.
Contradicts
Therapeutic Potential of Natural Compounds for Brain Ischemia-Reperfusion Injury.
Abstract
Brain ischemia-reperfusion (I/R) injury, commonly occurring in ischemic stroke and post-cardiac arrest scenarios, results in complex secondary damage involving oxidative stress, inflammation, apoptosis, and blood-brain barrier (BBB) breakdown. Despite decades of research, no pharmacological agent has yet been clinically approved for post-I/R neuroprotection. Natural compounds have recently gained attention for their multimodal therapeutic potential, including antioxidant, anti-inflammatory, anti-apoptotic, and neuroregenerative effects. This review highlights nine promising candidates-resveratrol, curcumin, quercetin, berberine, ginkgolide B, baicalin, naringin, fucoidan, and astaxanthin-that exhibit efficacy in experimental models of I/R injury when administered after the insult. Their chemical structures, pharmacokinetics, and mechanisms of action are described in detail, focusing on key signaling pathways such as nuclear factor erythroid 2-related (Nrf2), nuclear factor kappa B (NF-
Contradicts
Murine model of minimally invasive nasal depot (MIND) technique for central nervous system delivery of blood-brain barrier-impermeant therapeutics.
Abstract
The blood-brain barrier (BBB) poses a substantial obstacle to the successful delivery of therapeutics to the central nervous system (CNS). The transnasal route has been extensively explored, but success rates have been modest due to challenges related to the precise anatomical placement of drugs, the small volumes that the olfactory cleft can accommodate and short drug residence times due to mucociliary clearance. Here, to address these issues, we have developed a surgical technique known as the minimally invasive nasal depot (MIND), which allows the accurate placement of depot drugs into the submucosal space of the olfactory epithelium of rats. This technique exploits the unique anatomy of the olfactory apparatus to enable transnasal delivery of drugs into the CNS, bypassing the BBB. In our rat model, a bony window is created in the animal snout to expose the submucosal space. Using the MIND technique, we have successfully delivered oligonucleotides to the CNS in Sprague-Dawley and Lo
Contradicts
Overexpression of BDNF by Astrocytes Targeted Delivery of mRNA Ameliorates Cognitive Impairment in Mouse Model of TBI.
Abstract
Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic development and plasticity. It is a promising therapeutic target for improving neurofunctional outcomes after traumatic brain injury (TBI). However, the delivery of BDNF faces several significant challenges including limited entry into the CNS due to blood-brain barrier (BBB), short half-life, and potential side effects. The use of viral vectors like AAV to deliver the BDNF gene directly to the brain has shown promise in animal models. However, issues with host immunogenicity and limited biodistribution remain. Herein, we report a successful restoration of cognitive function of a TBI mouse model by efficient delivery of BDNF mRNA loaded to a novel lipid nanoparticle (DA6 LNP). DA6 LNPs loaded with either luciferase mRNA or GFP mRNA were internalized by astrocytes and dose dependently expressed the corresponding protein. Two consecutive intravenous injections of DA6 LNPs loaded with BDNF mRNA to a TBI mouse mod
Contradicts
Behavioral and psychological symptoms of dementia (BPSD) and impaired cognition reflect unsuccessful neuronal compensation in the pre-plaque stage and serve as early markers for Alzheimer's disease in the APP23 mouse model.
Abstract
Recent research on Alzheimer's disease (AD) focuses on processes prior to amyloid-beta plaque deposition accounting for the progress of the disease. However, early mechanisms of AD are still poorly understood and predictors of the disease in the pre-plaque stage essential for initiating an early therapy are lacking. Behavioral and psychological symptoms of dementia (BPSD) and potentially impaired cognition may serve as predictors and early clinical diagnostic markers for AD. To investigate potential BPSD and cognitive impairments in association with neuronal cell development as such markers for AD in the pre-plaque stage, female APP23 mice at eight, 19 and 31 weeks of age and corresponding control animals were tested for BPSD (elevated zero maze; sucrose preference test), motor coordination (rotarod), spatial memory and reversal learning (Morris water maze) and hippocampal neurogenesis as a neuronal correlate for hippocampus-dependent behavior. To evaluate a potential therapeutic effec
Contradicts
Advances and Therapeutic Potential of Anthraquinone Compounds in Neurodegenerative Diseases: A Comprehensive Review.
Abstract
BACKGROUND: Rhubarb, traditionally used in China for neurological disorders, has recently attracted considerable scientific attention for its neuroprotective and cerebrovascular benefits. The main therapeutic components of rhubarb are anthraquinones, including emodin, aloe-emodin, chrysophanol, rhein, and physcion. Accumulating experimental evidence indicates that anthraquinones are of importance in neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. However, as a promising candidate for drug development, the mechanisms by which anthraquinones treat NDDs have not been systematically reviewed. Therefore, this article outlines the anti-neurodegenerative effects of anthraquinones, focusing on their molecular mechanisms. OBJECTIVE: This article reviews recent research progress of anthraquinones in NDDs, focusing on their potential targets and pathways to provide new ideas for the intervention and treatment of ND
Contradicts
Human umbilical cord mesenchymal stem cells therapy for Alzheimer's disease: a systematic review and meta-analysis of mouse models.
Abstract
OBJECTIVE: Given the limitations of current treatments for Alzheimer's disease (AD), this study aims to comprehensively evaluate the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) in AD mouse models through a systematic review and meta-analysis. Additionally, we explore the impact of transplantation dose and route on treatment outcomes to identify the optimal window for clinical application. METHODS: In accordance with the PRISMA guidelines, we systematically searched four major databases to identify randomized controlled trials involving hUCMSCs in AD mouse models. We used the standardized mean difference (SMD) to synthesize effect sizes and performed subgroup analyses based on pre-defined transplantation routes and doses. RESULTS: A total of 13 studies were included in the analysis. The meta-analysis revealed that hUCMSCs transplantation significantly improved spatial learning and memory in AD model mice, with a marked reduction in escape latency (SMD =
Contradicts
Modulation of mitochondrial quality by exercise mimetics: A potential strategy for the prevention and treatment of Alzheimer's disease.
Abstract
Decline in mitochondrial quality is a prominent pathological feature of Alzheimer's disease (AD), manifested by impaired energy metabolism, disrupted mitochondrial biogenesis, abnormal mitochondrial dynamics, and defective mitophagy. Increasing evidence indicates that mitochondrial dysfunction contributes to the exacerbation of amyloid-β (Aβ) deposition and tau protein hyperphosphorylation, thereby accelerating AD pathogenesis. Of particular interest, physical exercise has been shown to effectively enhance mitochondrial quality and help prevent or slow the progression of AD, largely through the activation of key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). However, regular physical activity may not be feasible for individuals in the prodromal or clinical stages of AD. In this context, exercise mimetics-compounds that pharmacologically simulate the molecular effects of exercise-have emerged as a promising alternative intervent
Contradicts
Plant-derived bioactive compounds modulate the gut microbiota in Alzheimer's disease: Metabolite signaling, neuroimmune circuits, and systems-level regulation.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — BDNF
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for BDNF from GTEx v10.
💉 Clinical Trials (17)Relevance: 76%
0
Active
Active
0
Completed
Completed
1,293
Total Enrolled
Total Enrolled
PHASE1
Highest Phase
Highest Phase
RECRUITING·NCT07027072 · NeuroBiogen Co., Ltd
114 enrolled · 2025-08-06 · → 2027-06-30
A randomized, double-blind, placebo-controlled, dose-finding Phase 2a clinical trial will be conducted to evaluate the efficacy and safety of KDS2010 in patients with Mild Cognitive Impairment (MCI) d
Mild Cognitive Impairment (MCI) Mild Dementia Alzheimer's Disease
KDS2010 Placebo
RECRUITING·NCT05500170 · State University of New York at Buffalo
50 enrolled · 2023-04-04 · → 2027-08-30
Poor sleep quality and short sleep duration may be a mechanistic component of cognitive impairment in older adults, associated with a decline in brain-derived neurotrophic factor. Increasing the avail
Cognitive Impairment Sleep Quality
Nicotinamide riboside Placebo
COMPLETED·NCT02862210 · Columbia University
17 enrolled · 2017-01-27 · → 2022-11-20
Frontotemporal dementia (FTD) is a progressive neurodegenerative illness that affects the frontal and anterior temporal lobes of the brain. Changes in behavior, including agitation, aggression, and re
Frontotemporal Dementia (FTD)
Lithium Carbonate Placebo
COMPLETED·NCT02512627 · Chang Gung Memorial Hospital
55 enrolled · 2015-01-30 · → 2018-01-29
This study aims to investigate and compare the intervention effects of combining exercise and cognitive training (either sequentially or simultaneously in a dual-task paradigm) in elderly with mild co
Mild Cognitive Impairment
Cognitive training Physical exercise
UNKNOWN·NCT05569083 · Azienda Ospedaliero-Universitaria Careggi
350 enrolled · 2020-10-01 · → 2023-09-30
Alzheimer's disease (AD) has a presymptomatic course which can last from several years to decades. Identification of subjects at an early stage is crucial for therapeutic intervention and possible pre
Cognitive Decline Mild Cognitive Impairment Alzheimer Disease
Genetic analysis of APOE and BDNF genes. EEG recording CSF collection and AD biomarker measurement
COMPLETED·NCT04299217 · Northumbria University
75 enrolled · 2019-11-04 · → 2020-03-17
This study aims to assess the effects of a single dose of Zynamite® on performance across a number of cognitive domains (attention, working memory, episodic memory, executive function), as well as dur
Cognitive Change Stress
Zynamite® Placebo
COMPLETED·NCT06225440 · University of Westminster
64 enrolled · 2022-09-01 · → 2023-12-31
The goal of this randomised cross-over trial is to learn about the effects of Levagen+® Palmitoylethanolamide (PEA) supplementation on cognition, wellness and well-being in young and healthy universit
Wellness, Psychological Well-Being, Psychological
Levagen+® Palmitoylethanolamide (PEA) Placebo
COMPLETED·NCT03576274 · Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
110 enrolled · 2019-10-10 · → 2024-09-15
A 12 weeks technology enhanced home exercise (TEHE) program using mobile technologies that provide immediate feedback and send reminder messages to improve exercise motivation is developed. Investigat
Cancer-related Problem/Condition Exercise Acupressure
Technology Enhanced Home Exercise (TEHE) Auricular Point Acupressure (APA) Mindfulness body scan (MBI)
COMPLETED·NCT01674790 · Marilyn MacKay-Lyons
22 enrolled · 2013-10-13 · → 2017-06-16
The objective of the 'Exploring potential synergistic effects of aerobic exercise and cognitive training on cognition after stroke' pilot trial is to investigate the combined effects of aerobic and co
Stroke
Aerobic training Cognitive training Range of motion exercise
NOT_YET_RECRUITING·NCT04231708 · Wayne State University
20 enrolled · 2026-10 · → 2028-12
This preliminary study is designed to evaluate mechanisms by which excitatory dorsolateral prefrontal cortex (dlPFC) repetitive transcranial magnetic stimulation (rTMS) (vs. sham) and pharmacological
Opioid Use Disorder
Yohimbine + Hydrocortisone Active rTMS Placebo
COMPLETED·NCT03493282 · Cognition Therapeutics
43 enrolled · 2018-03-28 · → 2020-10-16
Study to Evaluate the Safety and Tolerability of Oral CT1812 in Subjects with Mild to Moderate Alzheimer's Disease.
Alzheimer Disease
Active Treatment- CT1812 100 mg Active Treatment- CT1812 300 mg Placebo
COMPLETED·NCT05887388 · University of North Carolina, Chapel Hill
38 enrolled · 2021-09-10 · → 2022-02-27
This primary purpose of this study will be to (1) examine the feasibility and acceptability of transitional care focusing on care needs of skilled nursing facility (SNF) patients with dementia and the
Pathologic Processes
Connect-Home Plus
COMPLETED·NCT06239740 · Thammasat University
60 enrolled · 2022-12-24 · → 2023-01-24
The goal of this pilot Study and Randomized Controlled Trial is to investigate the impact of electroacupuncture on cognitive function, quality of life (QoL), and depression severity in patients with m
Major Depressive Disorders Cognitive Dysfunction
Electroacupuncture group Sham acupuncture
UNKNOWN·NCT00306124 · University Hospital Muenster
120 enrolled · 2006-01
This study aims to determine whether levodopa is effective in boosting learning and memory in healthy subjects and patients with dementia or Mild Cognitive Impairment.
We also examine in healthy subj
Alzheimer's Disease Mild Cognitive Impairment Healthy
Levodopa
UNKNOWN·NCT00753662 · Tel-Aviv Sourasky Medical Center
45 enrolled · 2008-11 · → 2012-11
The primary objective of this trial is to assess the ability of Transcranial Magnetic Stimulation with H2 coil to prefrontal and parieto-temporal cortex to improve cognitive performance in patients wi
Alzheimer's Disease
1Hz TMS with H2 coil 10Hz TMS with H2 coil to prefrontal and parieto-temporal cortex SHAM TMS with H2 coil
COMPLETED·NCT01805518 · Woodbury, Michel, M.D.
20 enrolled · 2011-06 · → 2012-03
Phosphodiesterase is a candidate for the Rx \& prevention of cognitive and psychotic disorders. Since caffeine targets primarily PDE4(Phosphodiesterase subtype 4), caffeine analogs have been developed
Adverse Mental/Physical Effects of Low Dose S. Tortuosum.
Scelectium Tortuosum
UNKNOWN·NCT05363228 · Charles University, Czech Republic
90 enrolled · 2021-08-01 · → 2023-01-30
The aim of this project is to estimate the effects of therapy with dance and movement and Tai Chi on irisin plasma levels, a myokine with proven neuroprotective effects, in the context of baseline lev
Memory Deficits Aging Cognitive Impairment
Therapy by Dance and Movement Tai Chi
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for BDNF.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
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🔮 Predictions
🔎 Predictions vs Observations4 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| Selective noradrenaline depletion in APP/PS1 transgenic mice will exacerbate synaptic deficits, demonstrating that interneuron dysfunction is secondary to broader neurotransmitter system collapse rath | Greater magnitude of synaptic impairment (measured by reduced EPSP slope, decreased spine density, and impaired LTP) in APP/PS1 mice with selective noradrenalin | — no observation — | open | 0.50 |
| Selective modulation of GluN2B-containing NMDA receptors will restore thalamocortical oscillatory coupling in neurodegeneration models, with altered GluN2B expression correlating with circuit dysfunct | Administration of GluN2B-selective antagonist (if unexpected enhancement needed) or ifenprodil/nethiergin antagonizing excessive GluN2B activity will normalize | — no observation — | pending | 0.45 |
| NMDA receptor antagonism will prevent synaptic depression but NOT prevent spine loss in Aβ models, distinguishing between NMDAR-dependent signaling cascades and structural Aβ toxicity | Memantine or D-AP5 treatment in Aβ-oligomer exposed hippocampal slices will preserve normal EPSP responses (preventing synaptic depression) while spine density | — no observation — | pending | 0.40 |
| Optogenetic activation of SST interneurons in Aβ-oligomer injected mice will selectively restore theta band oscillations to baseline levels, while optogenetic activation of PV interneurons will select | Measurable increase in theta (4-8 Hz) and gamma (30-100 Hz) oscillatory power specifically in hippocampal circuits of Aβ-treated mice following cell-type-specif | — no observation — | pending | 0.55 |
🔮 Falsifiable Predictions (4)
pendingconf 55%
Optogenetic activation of SST interneurons in Aβ-oligomer injected mice will selectively restore theta band oscillations to baseline levels, while optogenetic activation of PV interneurons will selectively restore gamma band oscillations
Predicted outcome: Measurable increase in theta (4-8 Hz) and gamma (30-100 Hz) oscillatory power specifically in hippocampal circuits of Aβ-treated mice following cell-t
Falsification: Either: (1) Optogenetic SST activation fails to increase theta power above Aβ-impaired baseline levels, OR (2) Optogenetic PV activation fails to increase gamma power, OR (3) Activation of one interne
openconf 50%
Selective noradrenaline depletion in APP/PS1 transgenic mice will exacerbate synaptic deficits, demonstrating that interneuron dysfunction is secondary to broader neurotransmitter system collapse rather than a primary Aβ effect
Predicted outcome: Greater magnitude of synaptic impairment (measured by reduced EPSP slope, decreased spine density, and impaired LTP) in APP/PS1 mice with selective no
Falsification: If noradrenaline depletion in APP/PS1 mice does NOT exacerbate synaptic deficits (i.e., synaptic impairment remains equal to or less than APP/PS1 alone), then the hypothesis that neurotransmitter dysf
pendingconf 45%
Selective modulation of GluN2B-containing NMDA receptors will restore thalamocortical oscillatory coupling in neurodegeneration models, with altered GluN2B expression correlating with circuit dysfunction severity
Predicted outcome: Administration of GluN2B-selective antagonist (if unexpected enhancement needed) or ifenprodil/nethiergin antagonizing excessive GluN2B activity will
Falsification: If pharmacological modulation of GluN2B-containing NMDA receptors FAILS to alter thalamocortical coherence (remaining outside normal range), OR if GluN2B expression levels show NO significant correlat
pendingconf 40%
NMDA receptor antagonism will prevent synaptic depression but NOT prevent spine loss in Aβ models, distinguishing between NMDAR-dependent signaling cascades and structural Aβ toxicity
Predicted outcome: Memantine or D-AP5 treatment in Aβ-oligomer exposed hippocampal slices will preserve normal EPSP responses (preventing synaptic depression) while spin
Falsification: If NMDAR blockade prevents BOTH synaptic depression AND spine loss, then the hypothesis that these are mechanistically distinct is disproven. Alternatively, if NMDAR blockade prevents neither, then th
📖 References (13)
- Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer.Colucci-D'Amato L et al.. Int J Mol Sci (2020)
- Hyperactive neuronal autophagy depletes BDNF and impairs adult hippocampal neurogenesis in a corticosterone-induced mouse model of depression.["Zhang K" et al.. Theranostics (2023)
- Adult hippocampal neurogenesis and its impairment in Alzheimer's disease.["Kim T" et al.. Zoological research (2022)
- Functional Connectivity of Hippocampal CA3 Predicts Neurocognitive Aging via CA1-Frontal Circuit.["Liang X" et al.. Cerebral cortex (New York, N.Y. : 1991) (2020)
- Pharmacotherapy with fluoxetine restores functional connectivity from the dentate gyrus to field CA3 in the Ts65Dn mouse model of down syndrome.["Stagni F" et al.. PloS one (2013)
- Exercise therapy to prevent and treat Alzheimer's disease.["Pahlavani H"]. Frontiers in aging neuroscience (2023)
- Astrocytes and brain-derived neurotrophic factor (BDNF).Albini M et al.. Neuroscience research (2023)
- IL4-driven microglia modulate stress resilience through BDNF-dependent neurogenesis.["Zhang J" et al.. Science advances (2021)
- Hippocampal neural circuit mechanisms in Alzheimer's disease revealed by viral-genetic circuit mapping.["Ye Q" et al.. Neurobiology of disease (2025)
- Modulation of glymphatic system by visual circuit activation alleviates memory impairment and apathy in a mouse model of Alzheimer's disease.["Wu W" et al.. Nature communications (2025)
- Neuronal extracellular vesicles and associated microRNAs induce circuit connectivity downstream BDNF.["Antoniou A" et al.. Cell reports (2023)
- Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice.["Hong C" et al.. Acta pharmacologica Sinica (2023)
- Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment.Ruan S et al.. Journal of controlled release : official journal of the Controlled Release Society (2024)
▸Metadatasource: v1_phase_c_backfill · origin_type: gap_debate
| source | v1_phase_c_backfill |
| origin_type | gap_debate |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
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0 contradicting
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