Coordinated regional association of cathepsins and dipeptidyl peptidases with N-truncated Abeta42, Abeta40, and tau in Alzheimer’s brain

Regional distributions of amyloid-β (Aβ) and tau accumulation have provided important insights into the pathomechanisms of Alzheimer’s disease (AD). While such analyses have typically been conducted through histochemical or clinical imaging studies, we previously reported unique regional associations among Aβ species, tau and other proteins by biochemically analyzing multiple postmortem brain regions. Here, using a new cohort and novel ELISAs, we investigated the regional relationships of Aβ species, tau, neuroglial markers, cathepsins and dipeptidyl peptidases (DPP) across AD stages. Despite a relatively small sample size, this study replicated key prior findings, including a strong regional association between Aβ_1-42 and the postsynaptic maker PSD95 particularly in the early stage, distinct regional distributions of Aβ_1-42 and N-terminally truncated Aβ42 (Aβ_t-42), and a significant association between Aβ_t-42 and tau in AD. Moreover, this study observed that Aβ_1-42 was associated with other synaptic proteins, but not neurofilament proteins. Notably, several proteases, particularly cathepsin B, cathepsin D and DPPIV, exhibited strong regional correlations with total Aβ_x-42, Aβ_t-42, Aβ_x-40, and tau accumulations in AD, forming coordinated regional distribution patterns. Such strong regional associations with late-stage Aβ species and tau were not observed for neuroglial markers. At the microscopic level, these proteases displayed abnormal morphologies proximity to Aβ and tau pathologies. Their coordinated regional distributions with Aβ_t-42, Aβ_x-40, and tau may indicate that these proteases cooperatively promote neurodegenerative cascades in AD.