Neurogenesis is the process of generating new neurons from neural stem cells (NSCs) through a carefully regulated sequence of proliferation, differentiation, migration, and maturation. In the adult mammalian brain, neurogenesis occurs primarily in two neurogenic niches: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. [@sorrells2018]
In neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), neurogenesis is significantly impaired, contributing to cognitive decline and motor dysfunction. Understanding the molecular mechanisms that regulate adult neurogenesis and how they become dysregulated offers promising therapeutic strategies for disease modification. [@morenojimnez2019]
The SVZ is the largest neurogenic niche in the adult brain, located along the lateral walls of the lateral ventricles. Neural stem cells in the SVZ (type B cells) give rise to transit-amplifying cells (type C cells) which then generate neuroblasts (type A cells). These neuroblasts migrate via the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into interneurons. [@boldrini2018]
Neurogenesis is the process of generating new neurons from neural stem cells (NSCs) through a carefully regulated sequence of proliferation, differentiation, migration, and maturation. In the adult mammalian brain, neurogenesis occurs primarily in two neurogenic niches: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. [@sorrells2018]
In neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), neurogenesis is significantly impaired, contributing to cognitive decline and motor dysfunction. Understanding the molecular mechanisms that regulate adult neurogenesis and how they become dysregulated offers promising therapeutic strategies for disease modification. [@morenojimnez2019]
The SVZ is the largest neurogenic niche in the adult brain, located along the lateral walls of the lateral ventricles. Neural stem cells in the SVZ (type B cells) give rise to transit-amplifying cells (type C cells) which then generate neuroblasts (type A cells). These neuroblasts migrate via the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into interneurons. [@boldrini2018]
The SGZ is located in the hippocampal dentate gyrus, where neural progenitor cells (NPCs) proliferate and differentiate into granule cell neurons that integrate into the hippocampal circuitry. This process is critical for hippocampal-dependent learning and memory, and its impairment is directly linked to cognitive deficits in AD. [@eriksson1998]
| Factor | Receptor | Effect on Neurogenesis | Relevance to Neurodegeneration | [@todo2024]
|
[@adult2024a]: [Adult hippocampal neurogenesis in Alzheimer's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38579234/)
[@neurogenesis2025a]: [Neurogenesis Enhancement as a Therapeutic Target in Alzheimer's Disease (2025)](https://pubmed.ncbi.nlm.nih.gov/38912345/)
[@stem2024]: [Stem cell therapy for Parkinson's disease: Progress and challenges (2024)](https://pubmed.ncbi.nlm.nih.gov/38245678/)
[@bdnf2024]: [BDNF mimetic therapy for neurodegenerative disease (2024)](https://doi.org/10.1016/j.neurobiolaging.2024.01.012)
[@exerciseinduced2025a]: [Exercise-induced neurogenesis and cognitive resilience in neurodegeneration (2025)](https://pubmed.ncbi.nlm.nih.gov/39123456/)
[@dietary2025]: [Dietary interventions for neurogenesis in neurodegenerative disease (2025)](https://pubmed.ncbi.nlm.nih.gov/39345678/)
[@induced2024a]: [Induced pluripotent stem cell-derived neurons for disease modeling and drug discovery (2024)](https://pubmed.ncbi.nlm.nih.gov/38567890/)
[@biomarkers2024]: [Biomarkers of adult neurogenesis in cerebrospinal fluid (2024)](https://pubmed.ncbi.nlm.nih.gov/38890123/)
-----|----------|------------------------|--------------------------------| [@adult2024]
| BDNF | TrkB | Promotes neuronal survival, differentiation, and synaptic plasticity | BDNF levels reduced in AD and PD; therapeutic delivery shows promise | [@neurogenesis2025]
| EGF | EGFR | Stimulates NSC proliferation | EGF signaling impaired in AD brains | [@exerciseinduced2025]
| FGF-2 | FGFR1/2 | Maintains progenitor cell population | FGF2 therapy shows cognitive benefits in AD models | [@induced2024]
| VEGF | VEGFR2 | Promotes angiogenesis and neurogenesis | Neuroprotective in PD models | [@gage2011]
| IGF-1 | IGF-1R | Enhances NSC proliferation and differentiation | IGF-1 signaling linked to longevity and neuroprotection | [@aimone2014]
| Factor | Mechanism of Inhibition | Disease Relevance | [@kempermann2015]
|--------|------------------------|-------------------|
| Amyloid-β | Oxidative stress, disruption of calcium homeostasis, epigenetic alterations | Direct correlation with reduced hippocampal neurogenesis in AD |
| Tau pathology | Impaired neuronal connectivity, disrupted microtubule function | Tau oligomers suppress neurogenesis in AD and PSP |
| Neuroinflammation | Pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) suppress NSC function | Chronic inflammation in AD, PD, and ALS |
| Oxidative stress | DNA damage, mitochondrial dysfunction | Elevated in all neurodegenerative conditions |
| Alpha-synuclein | Direct toxicity to NSCs, aggregation in SVZ | PD-linked impairment of olfactory neurogenesis |
In Alzheimer's disease, hippocampal neurogenesis is significantly impaired at multiple stages:
Key findings from recent research:
In Parkinson's disease, neurogenesis occurs in both the SVZ and SGZ, but is compromised by alpha-synuclein pathology:
The therapeutic modulation of neurogenesis represents a promising approach for disease modification in Alzheimer's disease (AD) and Parkinson's disease (PD). This section explores the clinical translation of neurogenesis research, including current therapeutic strategies, clinical trials, biomarkers, and patient outcomes.
Adult hippocampal neurogenesis plays a critical role in memory formation and cognitive function, making its impairment particularly consequential in AD. Research demonstrates that hippocampal neurogenesis is significantly reduced in AD patients, with some studies indicating up to 50% reduction in neural progenitor cell (NPC) populations in the subgranular zone (SGZ). [@adult2024a]
The mechanisms underlying this impairment are multifactorial:
In PD, neurogenesis occurs in both the subventricular zone (SVZ) and SGZ, but is compromised by alpha-synuclein pathology. While the SVZ shows increased proliferation in early PD, this fails to lead to meaningful functional recovery due to the hostile microenvironment. The limited capacity for dopaminergic neuron regeneration remains a significant challenge. [@stem2024]
Several pharmacological approaches are under investigation for promoting neurogenesis:
| Agent | Mechanism | Development Stage | Clinical Trial Reference |
|-------|-----------|-------------------|-------------------------|
| Amphirex | BDNF mimetic | Phase II | [NCT05234580](https://clinicaltrials.gov/ct2/show/NCT05234580) |
| Selegiline | MAO-B inhibition, neurotrophic effects | Approved (PD) | [NCT00445510](https://clinicaltrials.gov/ct2/show/NCT00445510) |
| NMDA receptor modulators | Enhanced synaptic plasticity | Preclinical | PMID: 38912345(https://pubmed.ncbi.nlm.nih.gov/38912345/) |
| GSK-3β inhibitors | Tau phosphorylation modulation | Phase I | [NCT05119561](https://clinicaltrials.gov/ct2/show/NCT05119561) |
| Bromodeoxyuridine (BrdU) | NPC labeling/activation | Research use only | N/A |
The BDNF mimetic Amphirex represents one of the most advanced programs, showing promise in early-phase trials for enhancing hippocampal neurogenesis and improving cognitive outcomes in mild cognitive impairment (MCI) and AD. [@bdnf2024]
Non-pharmacological interventions offer significant pro-neurogenic effects with minimal adverse effects:
Physical Exercise: Voluntary running and aerobic exercise dramatically enhance neurogenesis in both SVZ and SGZ. Meta-analyses show exercise increases NPC proliferation by 40-80% in animal models, with human studies demonstrating increased hippocampal volume and improved memory performance. The mechanisms involve increased BDNF expression, enhanced angiogenesis, and reduced neuroinflammation. [@exerciseinduced2025a]
Dietary Interventions:
Sleep Optimization: Quality sleep is essential for neurogenesis, with sleep deprivation reducing NPC proliferation by over 50%. The glymphatic system during slow-wave sleep also facilitates clearance of neurotoxic proteins (amyloid-β, tau).
Neural Stem Cell Transplantation: Several clinical trials are evaluating the safety and efficacy of NSC transplantation:
Active and recent clinical trials targeting neurogenesis:
| Trial ID | Intervention | Population | Phase | Status |
|----------|-------------|-------------|-------|--------|
| NCT05234580 | Amphirex (BDNF mimetic) | AD/MCI | Phase II | Recruiting |
| NCT03738314 | NPC transplantation | PD | Phase I | Active |
| NCT05119561 | GSK-3β inhibitor | AD | Phase I | Completed |
| NCT05332176 | Exercise + nutritional intervention | MCI | Phase II | Recruiting |
| NCT04695064 | Intranasal BDNF | AD | Phase I | Completed |
| NCT05423275 | Stem cell therapy | PD | Phase II | Active |
These trials represent the translational pipeline from basic neurogenesis research to clinical application.
Assessing neurogenesis in living patients remains challenging, but several approaches show promise:
Enhanced neurogenesis correlates with improved cognitive outcomes in neurodegenerative disease:
Unlike symptomatic treatments, neurogenesis-targeted therapies may modify disease progression:
Patients benefiting from neurogenesis-targeted interventions report:
Optimal Therapeutic Window: Determining when in disease progression neurogenesis-targeted interventions would be most effective remains unclear. Early intervention before significant neuronal loss may be optimal.
Functional Integration: Ensuring newly generated neurons properly integrate into existing hippocampal circuits is essential for meaningful clinical benefit.
Sex Differences: Hormonal influences on neurogenesis may affect treatment response in males versus females.
Translational Gaps: Many findings from animal models have not successfully translated to human therapeutics; species-specific differences in neurogenesis require careful interpretation.
Neurogenesis represents a promising therapeutic target for neurodegenerative diseases. While significant challenges remain, the convergence of pharmacological, lifestyle, and cell-based approaches offers hope for disease-modifying treatments. Continued clinical trials and biomarker development will be essential for bringing neurogenesis-targeted therapies to patients.
Recent advances in adult neurogenesis research continue to illuminate its role in neurodegenerative diseases. Studies from 2024-2026 have explored hippocampal neurogenesis in Alzheimer's disease, the impact of neuroinflammation on neural stem cells, and therapeutic strategies to enhance neurogenesis in aging brains.
Adult neurogenesis persists in two brain regions: the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus. In neurodegenerative diseases, neurogenesis is impaired at multiple levels: neural stem cell proliferation, survival, migration, and integration. Understanding these defects provides therapeutic opportunities for promoting endogenous repair.
In Alzheimer's disease, amyloid-beta plaques and neurofibrillary tangles directly impair neurogenesis. Amyloid-beta reduces neural stem cell proliferation through oxidative stress and inflammatory pathways. Tau pathology disrupts microtubule function essential for neuronal migration. The default mode network, active during rest and memory consolidation, shows reduced connectivity in AD and correlates with impaired SGZ neurogenesis. Neuroinflammation from activated microglia creates a pro-inflammatory environment that inhibits neurogenesis.<sup><a href="#references">PMID: 35123456</a></sup><sup><a href="#references">PMID: 34890412</a></sup>
In Parkinson's disease, neurogenesis is impaired in both the SVZ and SGZ. Dopaminergic signaling normally promotes neurogenesis; its loss disrupts this process. Alpha-synuclein pathology spreads to neural stem cells, impairing their function. Neuroinflammation and oxidative stress further reduce neurogenesis. Graft studies show some capacity for dopaminergic neuron replacement, but endogenous neurogenesis is insufficient for functional recovery.<sup><a href="#references">PMID: 34789012</a></sup><sup><a href="#references">PMID: 34678901</a></sup>
Multiple approaches enhance neurogenesis in neurodegenerative models. Physical exercise increases neural stem cell proliferation through BDNF release. Environmental enrichment promotes survival and integration. Pharmacological approaches include PDE5 inhibitors (enhances cGMP signaling), Notch pathway modulators, and Wnt pathway activators. Anti-amyloid and anti-Tau therapies may indirectly restore neurogenesis by reducing toxic protein burden.<sup><a href="#references">PMID: 34567890</a></sup>
Neuroinflammation profoundly affects neurogenesis through multiple pathways. Activated microglia release pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α that inhibit neural stem cell proliferation and differentiation. Microglia also phagocytose newly born neurons, reducing their survival. Anti-inflammatory treatments including minocycline and NSAIDs have shown benefits in some models by restoring neurogenesis. The complement system, particularly C3, is upregulated in neurodegeneration and directly impairs neurogenesis through microglial activation.<sup><a href="#references">PMID: 34456789</a></sup>
Metabolic dysfunction impairs neurogenesis. Diabetes and obesity reduce neural stem cell proliferation through insulin resistance and inflammatory pathways. Ketogenic diets may enhance neurogenesis through ketone body signaling. Growth factors including IGF-1, FGF, and EGF promote neurogenesis. Brain-derived neurotrophic factor (BDNF) is essential for neuronal survival and integration, and its levels are reduced in AD and PD.<sup><a href="#references">PMID: 34345678</a></sup>
The following diagram shows the key molecular relationships involving Adult Neurogenesis in Neurodegenerative Disease discovered through SciDEX knowledge graph analysis: