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Hippocampal neurogenesis and pro-neurogenic therapies for Alzheimer's disease.

ABSTRACT: Adult hippocampal neurogenesis (AHN) facilitates hippocampal circuits plasticity and regulates hippocampus-dependent cognition and emotion. However, AHN malfunction has been widely reported in both human and animal models of Alzheimer's disease (AD), the most common form of dementia in the elderly. Pro-neurogenic therapies including rescuing innate AHN, cell engraftment and glia-neuron reprogramming hold great potential for compensating the neuronal loss and rewiring the degenerated neuronal network in AD, but there are still great challenges to be overcome. This review covers recent advances in unraveling the involvement of AHN in AD and highlights the prospect of emerging pro-neurogenic remedies.

SUBMITTER: Zheng J

PROVIDER: S-EPMC8879631 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Hippocampal neurogenesis and pro-neurogenic therapies for Alzheimer's disease.

Zheng Jie J

Animal models and experimental medicine 20220206 1

Adult hippocampal neurogenesis (AHN) facilitates hippocampal circuits plasticity and regulates hippocampus-dependent cognition and emotion. However, AHN malfunction has been widely reported in both human and animal models of Alzheimer's disease (AD), the most common form of dementia in the elderly. Pro-neurogenic therapies including rescuing innate AHN, cell engraftment and glia-neuron reprogramming hold great potential for compensating the neuronal loss and rewiring the degenerated neuronal net ...[more]

PMID: 35229998

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Project description:BackgroundAdult hippocampal neurogenesis (AHN) is restricted under the pathological conditions of neurodegenerative diseases, especially in Alzheimer's disease (AD). The drop of AHN reduces neural circuit plasticity, resulting in the decrease of the generation of newborn neurons in dentate gyrus (DG), which makes it difficult to recover from learning/memory dysfunction in AD, therefore, it is imperative to find a therapeutic strategy to promote neurogenesis and clarify its underlying mechanism involved.MethodsAmyloid precursor protein/presenilin 1 (APP/PS1) mice were treated with photobiomodulation therapy (PBMT) for 0.1 mW/mm2 per day in the dark for 1 month (10 min for each day). The neural stem cells (NSCs) were isolated from hippocampus of APP/PS1 transgenic mice at E14, and the cells were treated with PBMT for 0.667 mW/mm2 in the dark (5 min for each time).ResultsIn this study, photobiomodulation therapy (PBMT) is found to promote AHN in APP/PS1 mice. The latent transforming growth factor-β1 (LTGFβ1) was activated in vitro and in vivo during PBMT-induced AHN, which promoted the differentiation of hippocampal APP/PS1 NSCs into newborn neurons. In particular, behavioral experiments showed that PBMT enhanced the spatial learning/memory ability of APP/PS1 mice. Mechanistically, PBMT-stimulated reactive oxygen species (ROS) activates TGFβ/Smad signaling pathway to increase the interaction of the transcription factors Smad2/3 with Smad4 and competitively reduce the association of Smad1/5/9 with Smad4, thereby significantly upregulating the expression of doublecortin (Dcx)/neuronal class-III β-tubulin (Tuj1) and downregulating the expression of glial fibrillary acidic protein (GFAP). These in vitro effects were abrogated when eliminating ROS. Furthermore, specific inhibition of TGFβ receptor I (TGFβR I) attenuates the DNA-binding efficiency of Smad2/3 to the Dcx promotor triggered by PBMT.ConclusionOur study demonstrates that PBMT, as a viable therapeutic strategy, directs the adult hippocampal APP/PS1 NSCs differentiate towards neurons, which has great potential value for ameliorating the drop of AHN in Alzheimer's disease mice.

Project description:BackgroundUsing drugs to modulate microglial function may be an effective way to treat disorders, such as depression, that involve impaired neurogenesis. Akebia saponin D (ASD) can cross the blood-brain barrier and exert anti-inflammatory and neuroprotective effects, so we wondered whether it might influence adult hippocampal neurogenesis to treat depression.MethodsWe exposed C57BL/6 mice to chronic mild stress (CMS) as a model of depression and then gave them ASD intraperitoneally once daily for 3 weeks. We investigated the effects of ASD on microglial phenotype, hippocampal neurogenesis, and animal behavior. The potential role of the peroxisome proliferator-activated receptor-gamma (PPAR-γ) or BDNF-TrkB pathway in the pro-neurogenesis and anti-depressant of ASD was identified using there inhibitors GW9662 and K252a, respectively. The neurogenic effects of ASD-treated microglia were evaluated using conditioned culture methods.ResultsWe found that CMS upregulated pro-inflammatory factors and inhibited hippocampal neurogenesis in dentate gyrus of mice, while inducing depressive-like behaviors. Dramatically, ASD (40 mg/kg) treatment reprogrammed an arginase (Arg)-1+ microglial phenotype in dentate gyrus, which increased brain-derived neurotrophic factor (BDNF) expression and restored the hippocampal neurogenesis, and partially ameliorated the depressive-like behaviors of the CMS-exposed mice. K252a or neurogenesis inhibitor blocked the pro-neurogenic, anti-depressant effects of ASD. Furthermore, ASD activated PPAR-γ in dentate gyrus of CMS mice as well as in primary microglial cultures treated with lipopolysaccharide. Blocking the PPAR-γ using GW9962 suppressed the ASD-reprogrammed Arg-1+ microglia and BDNF expression in dentate gyrus of CMS mice. Such blockade abolished the promoted effects of ASD-treated microglia on NSPC proliferation, survival, and neurogenesis. The pro-neurogenic and anti-depressant effects of ASD were blocked by GW9962.ConclusionThese results suggested that ASD acts via the PPAR-γ pathway to induce a pro-neurogenic microglia in dentate gyrus of CMS mice that can increase BDNF expression and promote NSPC proliferation, survival, and neurogenesis.

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Hippocampal neurogenesis and pro-neurogenic therapies for Alzheimer's disease.

Publications

Hippocampal neurogenesis and pro-neurogenic therapies for Alzheimer's disease.

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