Seed‐competent, high‐molecular‐weight Aβ species is abundantly extracted in the cerebrovasculature and meninges in Alzheimer’s disease

Abstract

AbstractBackgroundSoluble high‐molecular‐weight (HMW) amyloid β (Aβ) species extracted from autopsied brains of patients with Alzheimer’s disease (AD) have been demonstrated to exhibit a seeding potency to induce cerebral β‐amyloidosis. However, it remains unknown where Aβ seed species resides and how it propagates throughout human AD brains. Our objective is to detect Aβ seed in human AD brain cerebrovasculature and meninges that are enriched with cerebral amyloid angiopathy (CAA).MethodWe examined eight autopsied human AD brains with abundant CAA and eight AD brains without immunohistochemically detectable CAA. Tris‐buffered saline (TBS)‐soluble fractions from the brain parenchyma or meningeal tissues were separated by size‐exclusion chromatography (SEC) with Superdex 75 column, and the concentrations of Aβ in each SEC‐separated fraction were measured by enzyme‐linked immunosorbent assay (ELISA). The TBS‐soluble, high‐molecular‐weight Aβ‐positive fractions were stereotaxically injected into the unilateral hippocampus or cisterna magna of 3‐month‐old amyloid precursor protein (APP) transgenic (tg) mice, and Aβ deposition in the hippocampus was assessed after four months.ResultHMW Aβ species were detected in TBS‐soluble fractions of the meninges and cerebrovasculature isolated from human AD brains. The concentration of HMW Aβ species extracted from meninges and cerebrovasculature was significantly higher than that from brain parenchyma in the same cases. Meningeal HMW Aβ species induced a robust Aβ deposition in the hippocampus, the area of which was significantly higher than that from the same weight of brain parenchyma. Moreover, the concentration of HMW Aβ species in CAA‐rich AD brains with meninges removed was significantly higher than those of CAA‐minimal AD brains. Intracisternal injection of HMW Aβ species derived from human AD brains induced not only CAA but also Aβ plaque.ConclusionSeed competent Aβ species are more abundant in cerebrovasculature and meninges than in brain parenchyma, and may accumulate in CAA in human AD brains. The possibility that HMW Aβ species in CAA contributes to Aβ plaque formation warrants further investigation in future studies.