Shinohara_2025_Acta.Neuropathol.Commun__

Regional distributions of amyloid-beta (Abeta) 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 Abeta 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 Abeta 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 Abeta(1-42) and the postsynaptic maker PSD95 particularly in the early stage, distinct regional distributions of Abeta(1-42) and N-terminally truncated Abeta42 (Abeta(t-42)), and a significant association between Abeta(t-42) and tau in AD. Moreover, this study observed that Abeta(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 Abeta(x-42), Abeta(t-42), Abeta(x-40), and tau accumulations in AD, forming coordinated regional distribution patterns. Such strong regional associations with late-stage Abeta species and tau were not observed for neuroglial markers. At the microscopic level, these proteases displayed abnormal morphologies proximity to Abeta and tau pathologies. Their coordinated regional distributions with Abeta(t-42), Abeta(x-40), and tau may indicate that these proteases cooperatively promote neurodegenerative cascades in AD.