AD7c-NTP Impairs Adult Striatal Neurogenesis by Affecting the Biological Function of MeCP2 in APP/PSl Transgenic Mouse Model of Alzheimer's Disease

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.

Adult Neurogenesis of Teleost Fish Determines High Neuronal Plasticity and Regeneration

“…The AD7c-NTP is associated with neurodegeneration in AD, and suppression is partially mediated by the phosphorylation of MeCP2 at serine 421 (S421), in combination with DNA demethylation at GFAP, Nestin, and DCX promoter regions, which prevents MeCP2 from binding to its target cells and thus reducing transcription repression, and in turn induces gene expression. These genes may be involved in regeneration and determination of the fate of NSPCs (neural stem/progenitor cells) during striatum neurogenesis in adults [78].…”

Genome-Wide DNA Methylation in Early-Onset-Dementia Patients Brain Tissue and Lymphoblastoid Cell Lines

“…This gene encodes for a protein capable of binding methylated DNA and acting as a transcriptional repressor [55]. Although it is primarily linked to autism spectrum disorders, studies on animal models have indicated a potential association between MECP2 alterations and AD pathogenesis, as well as cognitive decline [56][57][58][59]. Moreover, recent research on humans suggests that MECP2 may unveil a novel etiopathogenetic mechanism of sporadic AD [60].…”

The Neuroepigenetic Landscape of Vertebrate and Invertebrate Models of Neurodegenerative Diseases

“…The authors suggested that this finding was due to de novo phosphorylation of MeCP2 after AD pathological injury, possibly acting to relieve transcriptional repression. 63 …”

“…The authors suggested that this finding was due to de novo phosphorylation of MeCP2 after AD pathological injury, possibly acting to relieve transcriptional repression. 63 The implications of changes in expression of "reader" proteins in the context of neurodegenerative diseases require further investigation.…”