Vascular smooth muscle cell dysfunction contribute to neuroinflammation and Tau hyperphosphorylation in Alzheimer disease

Despite the emerging evidence implying early vascular contributions to neurodegenerative syndromes, the role of vascular smooth muscle cells (VSMCs) in the pathogenesis of Alzheimer disease (AD) is still not well understood. Herein, we show that VSMCs in brains of patients with AD and animal models of the disease are deficient in multiple VSMC contractile markers which correlated with Tau accumulation in brain arterioles. Ex vivo and in vitro experiments demonstrated that VSMCs undergo dramatic phenotypic transitions under AD-like conditions, adopting pro-inflammatory phenotypes. Notably, these changes coincided with Tau hyperphosphorylation at residues Y18, T205, and S262. We also observed that VSMC dysfunction occurred in an age-dependent manner and that expression of Sm22α protein was inversely correlated with CD68 and Tau expression in brain arterioles of the 3xTg-AD and 5xFAD mice. Together, these findings further support the contribution of dysfunctional VSMCs in AD pathogenesis and nominate VSMCs as a potential therapeutic target in AD. [Display omitted] •Loss of VSMC contractile phenotypes correlates with Tau accumulation in brain arterioles•VSMC dysfunction promotes the hyperphosphorylation of Tau protein at multiple residues•VSMC dysfunction occurs in an age-dependent manner in brain arterioles of patients with AD•Vascular smooth muscle cell is a promising therapeutic target in AD Molecular neuroscience; Immunology; Omics