Contributions of major tau kinase activation and phospho-tau accumulationto cortical and hippocampal tangle formation and cognition in older adults

Abstract

[eng] Aberrant activation of tau kinases (tauK) has been proposed as a major step in tau hyperphosphorylation andmisfolding, and subsequent formation of neurofibrillary tangles (NFT) in Alzheimer’s disease (AD). However,evidence of tauK hyperactivation in actual AD brains is scarce and inconsistent, and their role in age-relatedcognitive decline remains undocumented. We evaluated activated/inhibited species of CDK5/p35/p25,GSK3α/β, and ERK1/2 as well as ten tau/phospho-tau (ptau) peptides (mapping Ser202, Thr217, Ser262, Ser305,and Ser404 phospho-residues) by Western blot or selected reaction monitoring proteomics, respectively, inpostmortem dorsolateral prefrontal cortex (DLPFC) and hippocampal samples of 150 participants from the RushMemory and Aging Project (MAP). Regression models and mediation analyses assessed the contributions of thesevariables to tau phosphorylation, NFT deposition and antemortem cognitive status of MAP participants. Surprisingly,greater p25 and p35 (indices for CDK5 activation) and lower pSer21/9-GSK3α/β (inhibited species)immunodensities were associated with lower ptau peptide amounts. Individuals with higher p25 cortical densitiesdisplayed better cognitive outcomes, particularly working memory. Statistical mediation analyses indicatedthat the beneficial effect of CDK5/p25 on cognition was mediated by lower densities of phospho-Thr217-tau andNFT deposition in DLPFC, and also identified Thr217 and Ser262 as the ptau sites with greatest influence in bothNFT accumulation and cognitive impairment. The present data suggest that tau hyperphosphorylation, tangledeposition, and the subsequent cognitive impairment do not rely on aberrant activation of major tauKs. Additionally,novel evidence was provided for the beneficial contribution of cortical CDK5/p25 to the maintenance ofworking memory.