Neurogenesis And Neurodegeneration is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Adult neurogenesis — the generation of new functional [neurons](/entities/neurons) from neural stem cells (NSCs) in the mature brain — was first demonstrated [@platelet]
conclusively in humans by Eriksson et al. in 1998 using bromodeoxyuridine (BrdU) incorporation to label dividing progenitor cells in the [@dual]
hippocampal dentate gyrus.[@neuromodulatory] This landmark finding overturned [@lifestyle]
the long-held dogma that the adult mammalian brain is incapable of generating new [neurons](/entities/neurons). Since then, it has become clear that impaired [@smallmoleculebased]
neurogenesis is a common hallmark across [neurodegenerative diseases](/diseases), contributing not only to neuronal loss but also to the [^6]
failure of endogenous repair mechanisms that might otherwise slow disease progression [@neuromodulatory]. [^7]
Neurogenesis And Neurodegeneration is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Adult neurogenesis — the generation of new functional [neurons](/entities/neurons) from neural stem cells (NSCs) in the mature brain — was first demonstrated [@platelet]
conclusively in humans by Eriksson et al. in 1998 using bromodeoxyuridine (BrdU) incorporation to label dividing progenitor cells in the [@dual]
hippocampal dentate gyrus.[@neuromodulatory] This landmark finding overturned [@lifestyle]
the long-held dogma that the adult mammalian brain is incapable of generating new [neurons](/entities/neurons). Since then, it has become clear that impaired [@smallmoleculebased]
neurogenesis is a common hallmark across [neurodegenerative diseases](/diseases), contributing not only to neuronal loss but also to the [^6]
failure of endogenous repair mechanisms that might otherwise slow disease progression [@neuromodulatory]. [^7]
Adult neurogenesis occurs in two principal neurogenic niches: the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ) lining the lateral ventricles. The progressive impairment of neurogenesis in diseases such as [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and [Huntington's disease](/mechanisms/huntington-pathway) has implications for cognitive decline, mood disorders, and olfactory dysfunction that accompany these conditions [@platelet]. [^8]
The subgranular zone lies at the inner border of the granule cell layer in the dentate gyrus of the [hippocampus](/brain-regions/hippocampus). Here, radial glia-like Type 1 neural stem cells (expressing [GFAP](/entities/glial-fibrillary-acidic-protein), [Sox2](/proteins/sox2-protein), and Nestin) give rise to transit-amplifying Type 2 progenitors, which differentiate into Type 3 neuroblasts (expressing doublecortin/DCX and PSA-NCAM), and ultimately mature into glutamatergic dentate granule neurons that integrate into existing hippocampal circuits.[@platelet] [^9]
Approximately 700 new neurons are estimated to be added to each human [hippocampus](/brain-regions/hippocampus) per day under normal conditions, based on carbon-14 birth-dating studies by Spalding et al. (2013). These new neurons are critical for pattern separation, spatial memory formation, and contextual fear conditioning — functions central to hippocampal processing and vulnerable in early [Alzheimer's disease](/diseases/alzheimers-disease) [@dual]. [@sorrells2018]
The subventricular zone lines the lateral walls of the lateral ventricles and is the largest neurogenic niche in the adult mammalian brain. [@boldrini2018]
It contains Type B neural stem cells and Type C transit-amplifying cells that proliferate and differentiate continuously. In rodents, [@tobin2019]
SVZ-derived neuroblasts (Type A cells) migrate along the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into [@serranopozo2026]
GABAergic and dopaminergic interneurons [@lifestyle]. [@van1999]
In humans, SVZ neurogenesis is prominent in early life but declines substantially with age, with the RMS becoming largely vestigial by adulthood. However, SVZ-derived progenitors may retain capacity for reactive neurogenesis following injury, making this niche therapeutically relevant [@smallmoleculebased]. [@favaro2015]
A 2021 study by Terreros-Roncal et al. in Science systematically examined postmortem human samples from patients with [ALS](/diseases/als), [Huntington's disease](/mechanisms/huntington-pathway), [Parkinson's disease](/diseases/parkinsons-disease), [dementia with Lewy bodies](/diseases/dementia-lewy-bodies), and [frontotemporal dementia](/diseases/frontotemporal-dementia). The study found that adult-born dentate granule
cells showed abnormal morphological development, altered expression of differentiation markers, and that the homeostasis of the neurogenic
niche was disrupted across all conditions examined. [Aging](/gaps/aging) and neurodegeneration reduced the phagocytic capacity of [microglia](/entities/microglia) demonstrated
that while thousands of immature neurons (DCX-positive) are identifiable in the dentate gyrus of neurologically healthy subjects up to the
ninth decade of life, the number and maturation of these neurons progressively declined as AD advanced.[@lifestyle]
The decline is attributable to multiple pathological factors:
In [Parkinson's disease](/diseases/parkinsons-disease), both SGZ and SVZ neurogenesis are affected, though the SVZ is particularly impaired due to the loss of dopaminergic innervation from the [substantia nigra](/brain-regions/substantia-nigra). Dopamine directly modulates SVZ progenitor proliferation through the D3 receptor, and degeneration of the nigrostriatal pathway leads to decreased Type C cell proliferation [^7].
[alpha-synuclein](/proteins/alpha-synuclein) aggregation disrupts normal neural stem cell function. Postmortem studies of PD brains have shown reduced numbers of proliferating cells in the SVZ. Reduced hippocampal neurogenesis may contribute to the non-motor symptoms of PD, including cognitive decline, depression, and anosmia (loss of smell, related to reduced olfactory bulb neurogenesis) [^8].
In [Huntington's disease](/mechanisms/huntington-pathway), the mutant [huntingtin](/proteins/huntingtin) protein causes complex disruptions to neurogenesis. In knock-in
mouse models, striatal progenitors display delayed cell cycle exit and expansion of the intermediate progenitor pool with overexpression of
the pluripotency factor Sox2. [In the adult brain, while basal SVZ neurogenesis may remain relatively intact, it cannot be upregulated in
response to injury, and striatal neuroblasts fail to mature into functional neurons due to a hostile microenvironment. Dentate gyrus
neurogenesis is impaired in R6/2 mouse models, paralleling the cognitive decline observed in HD patients [^9].
[BDNF](/proteins/bdnf) is one of the most potent regulators of adult neurogenesis (see [neurotrophic factors](/mechanisms/neurotrophic-factors). It is highly expressed in the [hippocampus](/brain-regions/hippocampus) and acts through its high-affinity receptor TrkB. Upon BDNF-TrkB binding, three major intracellular signaling cascades are activated: PI3K/Akt (cell survival), MAPK/ERK (neurogenesis and synaptogenesis), and PLC-gamma (long-term potentiation). Physical exercise can increase BDNF synthesis by approximately threefold in the human brain.[@smallmoleculebased]
BDNF expression is regulated downstream of the Sox2-Wnt pathway: SOX2 binds to bivalently marked promoters of neurogenic genes including BDNF to maintain the bivalent chromatin state, and BDNF expression is reduced in SOX2-deficient neural progenitors [@sorrells2018].
The canonical Wnt/beta-catenin pathway plays a central role in hippocampal neurogenesis (see [Wnt signaling](/mechanisms/wnt-signaling-pathway-neurodegeneration). Wnt ligands (particularly
Wnt3a, secreted by local [astrocytes](/cell-types/astrocytes) in the SGZ) activate beta-catenin, which in complex with TCF/LEF transcription
factors displaces Sox2 from the NeuroD1 promoter, triggering neuronal differentiation. Downregulation of Wnt signaling is associated with
the pathophysiology of AD, and pharmacological Wnt activators such as andrographolide (which inhibits GSK-3beta have shown promise in
restoring neurogenesis in AD mouse models.[^6]
Notch signaling is a master regulator of NSC maintenance and quiescence. Activation of Notch by its ligands (Delta-like 1/Dll1, Jagged1)
triggers release of the Notch intracellular domain (NICD), which translocates to the nucleus and forms a complex with Rbpj. The NICD-Rbpj
complex induces expression of transcriptional repressors Hes1 and Hes5, which repress proneural genes (Ascl1/Mash1, Neurogenin2) and
maintain cells in an undifferentiated, stem-like state. When Rbpj is genetically deleted in the adult mouse brain, all neural stem cells
differentiate, demonstrating that Notch signaling is absolutely required for NSC maintenance.[^7]
DCX is a microtubule-associated protein expressed by neuronal precursor cells and immature neurons. Neural precursor cells begin to
express DCX while actively dividing, and their neuronal daughter cells continue to express DCX for 2-3 weeks as the cells mature. DCX has
been validated as a reliable and specific marker that reflects levels of adult neurogenesis. However, a 2024 study using digital droplet PCR
revealed broader-than-expected expression of DCX transcript in both hippocampal and cortical cell populations, suggesting that DCX
expression alone may not exclusively indicate neurogenesis in all brain regions [@boldrini2018].
[Amyloid-Beta](/proteins/amyloid-beta) has a complex, dose-dependent relationship with neurogenesis:
[tau protein](/proteins/tau)/proteins/tau-protein) effects on neurogenesis are multifaceted:
Dopaminergic innervation from the [substantia nigra](/brain-regions/substantia-nigra) and ventral tegmental area directly modulates SVZ neurogenesis. Type C transit-amplifying cells express dopamine receptors, particularly the D3 receptor, which is the only dopamine receptor specifically expressed in neurogenic areas in both embryonic and postnatal brain [@tobin2019].
Dopamine increases proliferation of SVZ-derived cells by releasing EGF in a PKC-dependent manner. In [Parkinson's disease](/diseases/parkinsons-disease), degeneration of the nigrostriatal pathway reduces dopaminergic inputs to SVZ Type C cells, resulting in decreased progenitor cell proliferation. This may contribute to the anosmia seen in early PD and potentially to broader cognitive deficits.[^8]
Experimentally, reduced progenitor cell proliferation in PD models can be restored by administering the D3 receptor agonist pramipexole, which augments SVZ proliferation, enhances neuronal differentiation, and increases new neurons in the olfactory bulb [@serranopozo2026].
Neural stem cells undergo progressive functional decline with aging, characterized by metabolic abnormalities, disrupted protein quality control, mitochondrial dysfunction, reduced genetic stability, and diminished capacity for proliferation and differentiation [@van1999].
Quiescence as a protective mechanism: NSC quiescence restricts the number of stem cell divisions and is essential for long-term stem cell pool maintenance. Loss of quiescence results in an imbalance in progenitor cell populations, ultimately leading to premature stem cell depletion.
FOXO transcription factors: Loss of FOXO transcription factors, the downstream effectors of the insulin/IGF1 pathway, leads to premature exhaustion of the NSC pool. Deregulated nutrient signaling leads to abnormal and wasteful NSC activation followed by premature exhaustion, which is a major component of brain [aging](/gaps/aging).
Glucose metabolism (2024 breakthrough): Ruetz et al. (2024, Nature) conducted CRISPR-Cas9 knockout screens in young and old mouse NSCs and identified over 300 genes whose deletion reactivated aged NSCs. Most notably, knockout of Slc2a4 (encoding the glucose transporter GLUT4) improved activation of old but not young quiescent NSCs, revealing that glucose uptake increases in NSCs during aging and that transient glucose starvation restores old NSC activation capacity.[^9]
In March 2018, two studies published within weeks of each other reached diametrically opposing conclusions, igniting one of the most intense debates in modern neuroscience [@favaro2015].
Sorrells et al. (Nature, 2018) examined postmortem hippocampal tissue and reported that proliferating progenitors and young neurons in the dentate gyrus sharply decline in the first year of life, with no young neurons detected in adult samples (18-77 years). Their conclusion: dentate gyrus neurogenesis does not continue, or is extremely rare, in the adult human.[@sorrells2018]
Boldrini et al. (Cell Stem Cell, 2018) assessed whole autopsy hippocampi from healthy individuals aged 14-79 years and found similar numbers of intermediate neural progenitors and thousands of immature neurons across ages. Their conclusion: healthy older subjects display preserved neurogenesis throughout aging.[@boldrini2018]
The divergent findings were traced to critical methodological differences:
Tobin et al. (2019, Cell Stem Cell) further demonstrated that hippocampal neurogenesis persists through the tenth decade of life and is detectable even in patients with [mild cognitive impairment](/diseases/mci) and [Alzheimer's disease](/diseases/alzheimers-disease), studying 18 participants with a mean age of 90.6 years.[@tobin2019]
The controversy has been substantially resolved by a 2026 study in Nature using multiomic single-cell sequencing to analyze 355,997 nuclei from human postmortem hippocampi across young adults, aged adults, SuperAgers, and individuals with AD. The study identified neural stem cells, neuroblasts, and immature granule neurons, confirming adult human hippocampal neurogenesis at the transcriptomic level. Dysregulated neurogenesis was largely associated with changes in chromatin accessibility, with early alterations evident in preclinical AD.[@serranopozo2026]
Voluntary physical exercise is the most robustly validated non-pharmacological enhancer of adult hippocampal neurogenesis. The seminal work of van Praag et al. (1999, Nature Neuroscience) demonstrated that mice with access to a running wheel showed enhanced progenitor proliferation, neuronal differentiation, and survival in the dentate gyrus.[@van1999]
In humans, moderate-intensity aerobic exercise (60-70% of maximum heart rate, 30-40 minutes, 3-4 times per week) optimally stimulates [BDNF](/proteins/bdnf) production and hippocampal neurogenesis. Critically, Choi et al. (2018, Science) demonstrated that in the 5xFAD Alzheimer's mouse model, neither stimulation of neurogenesis alone nor exercise without neurogenesis ameliorated cognition — only the combination of neurogenesis plus BDNF (mimicking exercise) provided cognitive benefit.[@smallmoleculebased]
Several pharmacological agents show promise:
Approaches to leveraging NSCs therapeutically include:
Multiomic resolution of the neurogenesis debate (2026): Single-cell sequencing of 355,997 nuclei confirmed adult hippocampal neurogenesis at the transcriptomic level and identified chromatin accessibility changes as early drivers of neurogenic decline in preclinical AD.[@serranopozo2026]
CRISPR screens reveal aging regulators in NSCs (2024): Ruetz et al. identified GLUT4 (Slc2a4) as a key regulator, demonstrating that glucose uptake increases in aging NSCs and that GLUT4 knockout restores activation capacity.[^9]
Cross-species neurogenesis atlas (2025): Two Nature Neuroscience studies revealed that immature dentate granule cells across species converge onto common biological processes for neuronal development but employ largely species-specific gene expression programs, cautioning against direct translation of rodent findings to humans.
Impact of neurodegenerative diseases across the neurogenic cascade (2021): Terreros-Roncal et al. systematically characterized how five different neurodegenerative diseases disrupt adult hippocampal neurogenesis at multiple levels.[@dual]
| Feature | Alzheimer's Disease | Parkinson's Disease | ALS | FTD | Huntington's Disease |
|---------|---------------------|---------------------|-----|-----|----------------------|
| Primary NSC Defect | Proliferation reduced, differentiation impaired | Proliferation reduced, migration impaired | Limited evidence | Variable | Proliferation reduced, survival impaired |
| SGZ Neurogenesis | Severely reduced (70-80% reduction) | Moderate reduction (30-40%) | Minimal change | Variable | Severe reduction (60-70%) |
| SVZ Neurogenesis | Reduced | Reduced (particularly in striatum) | Not well studied | Minimal | Severely reduced |
| Key Molecular Triggers | Abeta, tau, Wnt dysregulation | Alpha-syn, BDNF reduction, dopamine loss | Unknown | TDP-43 (some cases) | Mutant Htt, BDNF reduction |
| Neurotrophic Support | BDNF reduced, NGF reduced | BDNF reduced, GDNF reduced | Variable | BDNF reduced | BDNF severely reduced, CREB dysfunction |
| Inflammatory Environment | Severe (IL-1beta, TNF-alpha) | Moderate | Variable | Variable | Severe |
| Therapeutic Potential | Exercise, BDNF enhancers | GDNF, exercise | Limited | Unknown | BDNF, exercise |
| Factor | AD | PD | ALS | FTD | HD | Role |
|--------|-----|-----|-----|-----|-----|------|
| BDNF | Severely reduced | Reduced | Reduced | Reduced | Severely reduced | Neuronal survival, neurogenesis |
| GDNF | Reduced | Severely reduced | Variable | Normal | Reduced | Dopaminergic neuron support |
| NGF | Reduced | Normal | Normal | Normal | Reduced | Cholinergic neuron support |
| VEGF | Dysregulated (elevated) | Elevated | Reduced | Normal | Dysregulated | Angiogenesis, neurogenesis support |
| FGF-2 | Reduced | Normal | Normal | Normal | Reduced | NSC proliferation |
Neurogenesis requires proper progression through the cell cycle. In neurodegenerative diseases, multiple mechanisms disrupt cell cycle control:
The study of Neurogenesis And Neurodegeneration has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
This section highlights recent publications relevant to this mechanism.
🟡 Moderate Confidence
| Dimension | Score |
|-----------|-------|
| Supporting Studies | 15 references |
| Replication | 33% |
| Effect Sizes | 25% |
| Contradicting Evidence | 100% |
| Mechanistic Completeness | 50% |
Overall Confidence: 57%
The following diagram shows the key molecular relationships involving Neurogenesis and Neurodegeneration discovered through SciDEX knowledge graph analysis: