Abstract
The processes by which neural stem cells (NSCs) and neural precursor cells (NPCs) transform into the characteristic lineages observed in Alzheimer's disease (AD) are poorly characterized. Understanding these processes is of critical importance due to the increased prevalence of AD and the lack of effective AD strategies. Here, we used immunohistochemistry and Western blot to find out if MeCP2 was phosphorylated at a specific amino acid residue, Serine 421 (S421), and activated in response to AD-induced damage in amyloid precursor protein (APP)/PSl transgenic mice, altering its nuclear to cytoplasmic shuttling. Epigenetic examinations combined with chromatin immunoprecipitation and methylated DNA immunoprecipitation revealed that the translocation of MeCP2 from the nucleus to cytoplasm led to the loss of lineage-specific gene promoters (such as Gfap, Nestin, and Dcx), decreased transcriptional repression, and the activation of gene expression. Immunofluorescence data demonstrated that neurogenic progenitors with high levels of active phosphorylated MeCP2 at S421 (MeCP2 pS421) possessed a high probability of development into doublecortin (DCX)-expressing cells. AD7c-NTP will control neurogenic progenitor regeneration through its effects on MeCP2 pS421, leading to altered lineage-specific gene expression. This adds to the growing list of biological effects of AD7c-NTP in the brain and highlights MeCP2 as relevant to the plasticity of neural cells in the AD mice striatum.
Highlights
Alzheimer’s disease (AD) is the major form of senile dementia, a debilitating neuronal disorder that impairs memory, language, executive functions, and visuospatial skills (Dubois et al, 2014)
A loss of Methyl-CpG binding protein 2 (MeCP2) in the nuclear fraction and elevated levels of MeCP2 pS421 in the cytoplasmic fraction were observed in amyloid precursor protein (APP)/PSl transgenic mice (Figure 1C)
We demonstrate that AD7c-NTP is a regulatory factor for nerve regeneration in AD mice
Summary
AD is the major form of senile dementia, a debilitating neuronal disorder that impairs memory, language, executive functions, and visuospatial skills (Dubois et al, 2014). The expression and phosphorylation of MeCP2 and the regulation of its activity have not been investigated or characterized in AD We defined these properties in vivo and assessed their roles in the differentiation direction of NSCs/NPCs. MeCP2 was observed to undergo dynamic de novo phosphorylation at serine 421 (S421) following AD injury, highlighting its functionality in early AD stages in the mouse brain. The epigenetic modifications in such lineagespecific gene promoters may be involved in the regeneration and fate determination of NSCs/NPCs in the striatum of AD mice following AD7c-NTP inhibition This provides a platform to investigate the epigenetic mechanisms in regulating neurogenesis and differentiation in the AD mouse striatum
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