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

Aberrant activation of tau kinases (tauK) has been proposed as a major step in tau hyperphosphorylation and misfolding, 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-related cognitive 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, in postmortem dorsolateral prefrontal cortex (DLPFC) and hippocampal samples of 150 participants from the Rush Memory and Aging Project (MAP). Regression models and mediation analyses assessed the contributions of these variables to tau phosphorylation, NFT deposition and antemortem cognitive status of MAP participants. Surprisingly, greater p25 and p35 (indices for CDK5 activation) and lower pSer^21/9-GSK3α/β (inhibited species) immunodensities were associated with lower ptau peptide amounts. Individuals with higher p25 cortical densities displayed better cognitive outcomes, particularly working memory. Statistical mediation analyses indicated that the beneficial effect of CDK5/p25 on cognition was mediated by lower densities of phospho-Thr²¹⁷-tau and NFT deposition in DLPFC, and also identified Thr²¹⁷ and Ser²⁶² as the ptau sites with greatest influence in both NFT accumulation and cognitive impairment. The present data suggest that tau hyperphosphorylation, tangle deposition, 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 of working memory.