Pericyte loss: a key factor inducing brain Aβ40 accumulation and neuronal degeneration in cerebral amyloid angiopathy.

Abstract

Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease common among the elderly. Pericyte loss is one of the earliest characteristics of CAA. Although pericyte loss correlates with neuronal loss, the molecular mechanisms by which pericyte loss contributes to neurodegeneration and CAA progression remain poorly understood. This study aimed to explore the role and the mechanism of pericyte loss in CAA using in vivo APP/PS1 mice models and an in vitro neurovascular unit (NVU) model. The findings showed that pericyte coverage and mRNA expression levels of pleiotrophin (PTN) were significantly decreased in the brain of APP/PS1 mice compared with wild-type (WT) littermate mice, while the amyloid-beta peptide (Aβ) load was elevated. Both pericyte loss and Aβ40 fibrils increased the permeability of the blood-brain barrier (BBB) and decreased secretion of PTN in the in vitro NVU model. Notably, pericyte reintroduction attenuated Aβ40-induced apoptosis in all SH-SY5Y neuroblastoma cells across experimental models, and pericytes reversed the apoptosis of SH-SY5Y cells induced by Aβ40 fibrils in these models. Furthermore, Aβ40 fibrils downregulated PTN secretion and induced pericyte apoptosis through activation of the p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) signaling pathways. Collectively, these data suggest that BBB disruption resulting from pericyte loss serves as an early pathological hallmark in CAA, promoting Aβ40 accumulation and neurodegeneration via MAPK-dependent pathways. These findings highlight the therapeutic potential of pericyte preservation strategies in CAA management.