Brain Region-specific Accumulation of Amyloidosis-associated Proteins in Postmortem Brain Tissues of Alzheimer’s Disease Patients

Numerous extracellular matrix (ECM) proteins, referred to as the matrisome, are increased in Alzheimer’s disease (AD). We recently demonstrated that many of these proteins colocalize with Aβ plaques and cerebral amyloid angiopathy (CAA), and some are present in dystrophic cellular processes within and around plaques. However, their precise roles in AD pathogenesis and their spatial and temporal distribution in postmortem brain tissue remain incompletely understood. Here, we performed a comprehensive immunohistochemistry analysis on postmortem brain samples spanning the spectrum of AD neuropathological change (ADNC: low, intermediate, and high). We assessed the accumulation of five matrisome proteins (MDK, SPOCK3, COL25aA1, SDC4, and EGFL8) across four brain regions differentially affected in AD (occipital cortex, hippocampus, striatum, and cerebellum), and examined their association with Aβ plaques, CAA, tau neurites, and neurofibrillary tangles (NFT). MDK in plaques increased consistently with ADNC severity across all regions. In contrast, SPOCK3, COL25A1, EGFL8, and SDC4 showed marked accumulation only in the occipital cortex and hippocampus, with sparse presence in the striatum and absence in the cerebellum. Notably, SPOCK3 exhibited pronounced regional specificity, with significantly higher levels in the hippocampus than in other areas. Patterns of plaque staining and degree of colocalization indicate that select matrisome proteins associate with either distinct types of Aβ deposits (e.g, fibrillar and neuritic versus diffuse plaques), while others may correlate more closely with tau pathology and/or dystrophic processes around plaques. Overall, our findings reveal region- and pathology-specific patterns of these matrisome protein accumulation during AD progression. These proteins represent intriguing biomarkers of AD and based on modeling studies represent potential therapeutic targets.