Dataset Information

Systemic Factors Trigger Vasculature Cells to Drive Notch Signaling and Neurogenesis in Neural Stem Cells in the Adult Brain.

ABSTRACT: It is well documented that adult neural stem cells (NSCs) residing in the subventricular zone (SVZ) and the subgranular zone (SGZ) are induced to proliferate and differentiate into new neurons after injury such as stroke and hypoxia. However, the role of injury-related cues in driving this process and the means by which they communicate with NSCs remains largely unknown. Recently, the coupling of neurogenesis and angiogenesis and the extensive close contact between vascular cells and other niche cells, known as the neurovascular unit (NVU), has attracted interest. Further facilitating communication between blood and NSCs is a permeable blood-brain-barrier (BBB) present in most niches, making vascular cells a potential conduit between systemic signals, such as vascular endothelial growth factor (VEGF), and NSCs in the niche, which could play an important role in regulating neurogenesis. We show that the leaky BBB in stem cell niches of the intact and stroke brain can respond to circulating VEGF165 to drive induction of the Notch ligand DLL4 (one of the most important cues in angiogenesis) in endothelial cells (ECs), pericytes, and further induce significant proliferation and neurogenesis of stem cells. Stem Cells 2019;37:395-406.

SUBMITTER: Lin R

PROVIDER: S-EPMC7028145 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Systemic Factors Trigger Vasculature Cells to Drive Notch Signaling and Neurogenesis in Neural Stem Cells in the Adult Brain.

Lin Ruihe R Cai Jingli J Kenyon Lawrence L Iozzo Renato R Rosenwasser Robert R Iacovitti Lorraine L

Stem cells (Dayton, Ohio) 20181230 3

It is well documented that adult neural stem cells (NSCs) residing in the subventricular zone (SVZ) and the subgranular zone (SGZ) are induced to proliferate and differentiate into new neurons after injury such as stroke and hypoxia. However, the role of injury-related cues in driving this process and the means by which they communicate with NSCs remains largely unknown. Recently, the coupling of neurogenesis and angiogenesis and the extensive close contact between vascular cells and other niche ...[more]

PMID: 30431198

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Project description:BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease. However, there is no experimental evidence for a causal link between systemic inflammation or neuroinflammation and the onset of the disease. METHODS: The viral mimic, polyriboinosinic-polyribocytidilic acid (PolyI:C) was used to stimulate the immune system of experimental animals. Wild-type (WT) and transgenic mice were exposed to this cytokine inducer prenatally (gestation day (GD)17) and/or in adulthood. Behavioral, immunological, immunohistochemical, and biochemical analyses of AD-associated neuropathologic changes were performed during aging. RESULTS: We found that a systemic immune challenge during late gestation predisposes WT mice to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines, an increase in the levels of hippocampal amyloid precursor protein (APP) and its proteolytic fragments, altered Tau phosphorylation, and mis-sorting to somatodendritic compartments, and significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. These include deposition of APP and its proteolytic fragments, along with Tau aggregation, microglia activation and reactive gliosis. Whereas A? peptides were not significantly enriched in extracellular deposits of double immune-challenged WT mice at 15 months, they dramatically increased in age-matched immune-challenged transgenic AD mice, precisely around the inflammation-induced accumulations of APP and its proteolytic fragments, in striking similarity to the post-mortem findings in human patients with AD. CONCLUSION: Chronic inflammatory conditions induce age-associated development of an AD-like phenotype in WT mice, including the induction of APP accumulations, which represent a seed for deposition of aggregation-prone peptides. The PolyI:C mouse model therefore provides a unique tool to investigate the molecular mechanisms underlying the earliest pathophysiological changes preceding fibrillary A? plaque deposition and neurofibrillary tangle formations in a physiological context of aging. Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.

Dataset Information

Systemic Factors Trigger Vasculature Cells to Drive Notch Signaling and Neurogenesis in Neural Stem Cells in the Adult Brain.

Publications

Systemic Factors Trigger Vasculature Cells to Drive Notch Signaling and Neurogenesis in Neural Stem Cells in the Adult Brain.

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