Dysregulated calcium signaling in the aged macaque entorhinal cortex associated with tau hyperphosphorylation.

Abstract

Tau pathology in sporadic Alzheimers disease (AD) follows a distinct pattern, beginning in the entorhinal cortex (ERC) and spreading to interconnected brain regions. Early-stage tau pathology, characterized by soluble phosphorylated tau, is difficult to study in human brains post-mortem due to rapid dephosphorylation. Rhesus macaques, which naturally develop age-related tau pathology resembling human AD, provide an ideal model for investigating early tau etiology. This study examines the molecular processes underlying tau pathology in the macaque ERC, focusing on calcium and inflammatory signaling pathways. Our findings reveal age-related decreases in PDE4 phosphodiesterases that hydrolyze cAMP and increases in calpain-2 and GCPII that occur in parallel with early-stage tau hyperphosphorylation at multiple epitopes (pS214-tau, pT181-tau, pT217-tau). These findings suggest that dysregulated calcium signaling in ERC, beginning in middle-age, primes tau for hyperphosphorylation, potentially driving the early stages of AD, advancing our understanding of how ERC vulnerabilities contribute to neurodegeneration in AD.