Adult hippocampal neurogenesis in Alzheimer’s disease: A roadmap to clinical relevance

Salta, Evgenia; Lazarov, Orly; Fitzsimons, Carlos P.; Tanzi, Rudolph E.; Lucassen, Paul J.; Choi, Se Hoon

doi:10.1016/j.stem.2023.01.002

Cited by 47 publications

(33 citation statements)

References 215 publications

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“…One cellular manifestation of growth factor signaling activation is neurogenesis. Granule cells (GC) in the dentate gyrus (DG) of the hippocampus constitute the primary niche for adult hippocampal neurogenesis 28 . A more focused analysis of the snRNA-seq data within the hippocampal excitatory neurons revealed that exercise causes a more drastic gene expression change in the GC population than the pyramidal cell population ( Fig 5a-c ), leading to a higher proportion of granule cells within the EN cluster ( Fig 5d ).…”

Section: Resultsmentioning

confidence: 99%

Multi-omics delineate growth factor network underlying exercise effects in an Alzheimer’s mouse model

Li,

Liu,

et al. 2024

Preprint

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Physical exercise represents a primary defense against age-related cognitive decline and neurodegenerative disorders like Alzheimer's disease (AD). To impartially investigate the underlying mechanisms, we conducted single-nucleus transcriptomic and chromatin accessibility analyses (snRNA-seq and ATAC-seq) on the hippocampus of mice carrying AD-linked NL-G-F mutations in the amyloid precursor protein gene (APPNL-G-F) following prolonged voluntary wheel-running exercise. Our study reveals that exercise mitigates amyloid-induced changes in both transcriptomic expression and chromatin accessibility through cell type-specific transcriptional regulatory networks. These networks converge on the activation of growth factor signaling pathways, particularly the epidermal growth factor receptor (EGFR) and insulin signaling, correlating with an increased proportion of immature dentate granule cells and oligodendrocytes. Notably, the beneficial effects of exercise on neurocognitive functions can be blocked by pharmacological inhibition of EGFR and the downstream phosphoinositide 3-kinases (PI3K). Furthermore, exercise leads to elevated levels of heparin-binding EGF (HB-EGF) in the blood, and intranasal administration of HB-EGF enhances memory function in sedentary APPNL-G-F mice. These findings offer a panoramic delineation of cell type-specific hippocampal transcriptional networks activated by exercise and suggest EGF-related growth factor signaling as a druggable contributor to exercise-induced memory enhancement, thereby suggesting therapeutic avenues for combatting AD-related cognitive decline.

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Section: Resultsmentioning

confidence: 99%

Multi-omics delineate growth factor network underlying exercise effects in an Alzheimer’s mouse model

Li,

Liu,

et al. 2024

Preprint

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“…The structure and composition of such complex neurogenic niches have been best studied in the adult SVZ and include crosstalk between multiple distinct cell types (e.g., glia, neurons, endothelial cells, pericytes, microglia), extracellular elements (e.g., specialized extracellular matrix proteins), and intrinsic and extrinsic signaling elements 75 . Specifically, one of the key factors supporting and regulating NSC proliferation and differentiation in the SVZ, SGZ, and ME is their proximity to the vasculature 76–79 . Since all CVOs are characterized by increased BBB permeability, allowing access of peripheral circulating molecules, as well as by the presence of very dense fenestrated vasculature, it would be important to study the potential role of this unique CVO vasculature in the regulation of NSCs in sensory and secretory CVOs.…”

Section: Discussionmentioning

confidence: 99%

Constitutive cell proliferation and neurogenesis in the organum vasculosum lamina terminalis and subfornical organ of adult rats

Zhou,

Makashova,

Chevillard

et al. 2024

J Neuroendocrinology

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Neurogenesis continues throughout adulthood in the subventricular zone, hippocampal subgranular zone, and the hypothalamic median eminence (ME) and the adjacent medio‐basal hypothalamus. The ME is one of the circumventricular organs (CVO), which are specialized brain areas characterized by an incomplete blood–brain barrier and, thus, are involved in mediating communication between the central nervous system and the periphery. Additional CVOs include the organum vasculosum laminae terminalis (OVLT) and the subfornical organs (SFO). Previous studies have demonstrated that the ME contains neural stem cells (NSCs) capable of generating new neurons and glia in the adult brain. However, it remains unclear whether the OVLT and SFO also contain proliferating cells, the identity of these cells, and their ability to differentiate into mature neurons. Here we show that glial and mural subtypes exhibit NSC characteristics, expressing the endogenous mitotic maker Ki67, and incorporating the exogenous mitotic marker BrdU in the OVLT and SFO of adult rats. Glial cells constitutively proliferating in the SFO comprise NG2 glia, while in the OVLT, both NG2 glia and tanycytes appear to constitute the NSC pool. Furthermore, pericytes, which are mural cells associated with capillaries, also contribute to the pool of cells constitutively proliferating in the OVLT and SFO of adult rats. In addition to these glial and mural cells, a fraction of NSCs containing proliferation markers Ki67 and BrdU also expresses the early postmitotic neuronal marker doublecortin, suggesting that these CVOs comprise newborn neurons. Notably, these neurons can differentiate and express the mature neuronal marker NeuN. These findings establish the sensory CVOs OVLT and SFO as additional neurogenic niches, where the generation of new neurons and glia persists in the adult brain.

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“…Recently, RNA‐sequencing was adopted for investigating human adult neurogenesis in spite of the conflicting results 132‐134 . The disagreement between those studies might, to some extent, might be due to sample stratification and methodology 135 . Nevertheless, the differences between humans and mice are substantial and should not be overlooked.…”

Section: Identifications Of Rsa and Astrogliamentioning

confidence: 99%

“…[132][133][134] The disagreement between those studies might, to some extent, might be due to sample stratification and methodology. 135 Nevertheless, the differences between humans and mice are substantial and should not be overlooked. The average life expectancy of a human is over 70 years, whereas laboratory mice live 26-30 months on average; it is, therefore, critical to align the specific timing of the neurogenesis trajectory across species.…”

Section: Animal Models and Human Neurogenesismentioning

confidence: 99%

Radial stem astrocytes (aka neural stem cells): Identity, development, physio‐pathology, and therapeutic potential

Yeh

Huang

et al. 2023

Acta Physiologica

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Adult neurogenesis is a striking example of neuroplasticity, which enables adaptive network remodelling in response to all forms of environmental stimulation in physiological and pathological contexts. Dysregulation or cessation of adult neurogenesis contributes to neuropathology negatively affecting brain functions and hampering regeneration of the nervous tissue while targeting adult neurogenesis may provide the basis for potential therapeutic interventions. Neural stem cells in the adult mammalian brain are at the core and the entry point of adult neurogenesis. By their origin and properties, these cells belong to astroglia, and are represented by stem radial astrocytes (RSA) which exhibit multipotent “stemness”. In the neurogenic niches, RSA interact with other cellular components, including protoplasmic astrocytes, which in turn regulate their neurogenic activity. In pathology, RSA become reactive, which affects their neurogenic capabilities, whereas reactive parenchymal astrocytes up‐regulate stem cell hallmarks and are able to generate progeny that remain within astrocyte lineage. What makes RSA special is their multipotency, represented by self‐renewing capacity capability to generate other cellular types as progeny. A broad understanding of the cellular features of RSA and parenchymal astrocytes provides an insight into the machinery that promotes/suppresses adult neurogenesis, clarifying principles of network remodelling. In this review, we discuss the cellular hallmarks, research tools, and models of RSA and astrocytes of the subventricular zone along the lateral ventricle and dentate gyrus of the hippocampus. We also discuss RSA in ageing, which has a great impact on the proliferative capacity of RSA, as well as the potential of RSA and astrocytes in therapeutic strategies aimed at cell replacement and regeneration.

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Adult hippocampal neurogenesis in Alzheimer’s disease: A roadmap to clinical relevance

Cited by 47 publications

References 215 publications

Multi-omics delineate growth factor network underlying exercise effects in an Alzheimer’s mouse model

Multi-omics delineate growth factor network underlying exercise effects in an Alzheimer’s mouse model

Constitutive cell proliferation and neurogenesis in the organum vasculosum lamina terminalis and subfornical organ of adult rats

Radial stem astrocytes (aka neural stem cells): Identity, development, physio‐pathology, and therapeutic potential

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