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Soluble amyloid precursor protein-? rescues age-linked decline in neural progenitor cell proliferation.

ABSTRACT: Neurogenesis is thought to play a role in cognitive function and hippocampal plasticity. Previous studies suggest that neurogenesis declines with aging. However, the onset and mechanism of declined neurogenesis are not fully elucidated. Here we show that the major decline in neurogenesis takes place during adulthood, before aging. Decline in neurogenesis takes place in the subgranular layer of the dentate gyrus and in the subventricular zone, and is primarily due to a reduced number of fast-proliferating neural progenitor cells. Importantly, this decline can be rescued by intraventricular injection of recombinant soluble amyloid precursor protein (sAPP?), which regulates neural progenitor cell proliferation in the adult brain. The counterpart, sAPP?, a product of the amyloidogenic cleavage pathway of amyloid precursor protein, fails to exhibit a proliferative effect in vitro and in vivo, in equimolar concentrations to sAPP?. These observations suggest that adulthood is an appropriate time window for an intervention that upregulates neurogenesis, such as enhancement of sAPP? levels, for the prevention of declining brain plasticity and cognitive function.

SUBMITTER: Demars MP

PROVIDER: S-EPMC3706568 | biostudies-other | 2013 Oct

REPOSITORIES: biostudies-other

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Soluble amyloid precursor protein-α rescues age-linked decline in neural progenitor cell proliferation.

Demars Michael P MP Hollands Carolyn C Zhao Kai Da Tommy Kda T Lazarov Orly O

Neurobiology of aging 20130514 10

Neurogenesis is thought to play a role in cognitive function and hippocampal plasticity. Previous studies suggest that neurogenesis declines with aging. However, the onset and mechanism of declined neurogenesis are not fully elucidated. Here we show that the major decline in neurogenesis takes place during adulthood, before aging. Decline in neurogenesis takes place in the subgranular layer of the dentate gyrus and in the subventricular zone, and is primarily due to a reduced number of fast-prol ...[more]

PMID: 23683827

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Project description:IntroductionThe lack of regenerative capacity of the central nervous system is one of the major challenges nowadays. The knowledge of guidance cues that trigger differentiation, proliferation, and migration of neural stem and progenitor cells is one key element in regenerative medicine. The extracellular matrix protein tenascin-C (Tnc) is a promising candidate to regulate cell fate due to its expression in the developing central nervous system and in the adult neural stem cell niches. Of special interest are the alternatively spliced fibronectin type III (FnIII) domains of Tnc whose combinatorial diversity could theoretically generate up to 64 isoforms in the mouse. A total of 27 isoforms have already been discovered in the developing brain, among others the domain combinations A1D, CD, and A124BCD.MethodsIn the present study, these domains as well as the combination of the constitutively expressed FnIII domains 7 and 8 (78) were expressed in Chinese hamster ovary cells as pseudo-antibodies fused to the Fc-fragment of a human immunoglobulin G antibody. The fusion proteins were presented to primary mouse neural stem/progenitor cells (NSPCs) grown as neurospheres, either as coated culture substrates or as soluble additives in vitro. The influence of the domains on the differentiation, proliferation and migration of NSPCs was analyzed.ResultsWe observed that the domain combination A124BCD promoted the differentiation of neurons and oligodendrocytes, whereas the domain A1D supported astrocyte differentiation. The constitutively expressed domain 78 had a proliferation and migration stimulating impact. Moreover, most effects were seen only in one of the presentation modes but not in both, suggesting different effects of the Tnc domains in two- and three-dimensional cultures.DiscussionThis knowledge about the different effect of the Tnc domains might be used to create artificial three-dimensional environments for cell transplantation. Hydrogels spiked with Tnc-domains might represent a promising tool in regenerative medicine.

Dataset Information

Soluble amyloid precursor protein-? rescues age-linked decline in neural progenitor cell proliferation.

Publications

Soluble amyloid precursor protein-α rescues age-linked decline in neural progenitor cell proliferation.

Similar Datasets

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