Phosphorylation of MAP 1A regulates hyperphosphorylation of Tau in Alzheimer's disease model

• Published in: Neuropathology and applied neurobiology 2023-10, Vol.49 (5), p.e12934-n/a
• Main Authors: Cai, Biao, Shao, Nan, Ye, Ting, Zhou, Peng, Si, Wenwen, Song, Hang, Wang, Guangyun, Kou, Junping
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animal models; CDK5; Cell culture; Cell survival; Cyclin-dependent kinase 5; Immunoprecipitation; Kinases; MAP 1A; Molecular modelling; Neurodegenerative diseases; Pathogenesis; phosphoproteomics; Phosphorylation; Presenilin 1; Proteomics; siRNA; tau; Tau protein; Transgenic mice
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/nan.12934

Background and purpose Hyperphosphorylation of Tau is one of the important pathological features of Alzheimer's disease (AD). Therefore, studying the mechanisms behind Tau hyperphosphorylation is crucial in exploring the pathogenesis of neurological damage in AD. Methods In this study, after the establishment of rat models of AD, quantitative phosphoproteomics and proteomics were performed to identify proteins, showing that phosphorylation of microtubule associated protein 1A (MAP 1A) was lower in the model group. Western blot confirmed the changes of MAP 1A in the SD rats, APP/PS1 transgenic mice and cell AD models. To further study the molecular mechanism of recombinant MAP 1A phosphorylation affecting Tau phosphorylation, interfering siRNA‐MAP 1A and protein immunoprecipitation reaction analysis were performed in AD cell models. Results Cyclin‐dependent kinase 5 (CDK5) showed reduced binding to MAP 1A and increased binding to Tau, resulting in a decrease in phosphorylated MAP 1A (p‐MAP 1A) and an increase in phosphorylated Tau (p‐Tau), and MAP 1A silencing promoted binding of CDK5‐Tau and increased Tau phosphorylation, thereby reducing the cell survival rate. Conclusions In summary, we found that p‐MAP 1A downregulation associated with p‐Tau upregulation was due to their altered binding forces to CDK5, and MAP 1A could enhance autophosphorylation by competitive binding to CDK5 and antagonise Tau phosphorylation. This leads to neuronal protection and reducing tissue damage levels in AD, which can help better understand the mechanisms of AD pathogenesis. Quantitative proteomics and Quantitative phosphoproteomics were used to screen for the correlation between MAP1A phosphorylation and AD pathogenesis. MAP1A phosphorylation may be a new mechanism of AD pathogenesis, and its function is to reduce Tau phosphorylation by affecting binding ability of Tau with CDK5, thus affecting the occurrence of AD.