Abstract

Despite the emerging evidence implying early vascular contributions to neurogenerative syndromes, the role of vascular smooth muscle cells (VSMCs) in the pathogenesis of Alzheimers disease is still not well understood. Herein, we show that VSMCs in brains of AD patients and the animal model 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 and synthetic phenotypes. Notably, these changes coincided with Tau hyperphosphorylation at residues Y18, T205 and S262. We also observed that loss of VSMC markers occurred in an age-dependent manner, and that expression of Sm22 and -Sma proteins were inversely correlated with CD68 and Tau accumulation in brain arterioles of 3xTg-AD mice. Together, these findings further support the contribution of VSMCs in AD pathogenesis, and nominate VSMCs as potential novel therapeutic target in AD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/439741v1_ufig1.gif" ALT="Figure 1"> View larger version (87K): org.highwire.dtl.DTLVardef@8b1648org.highwire.dtl.DTLVardef@163dc88org.highwire.dtl.DTLVardef@123677borg.highwire.dtl.DTLVardef@15eed09_HPS_FORMAT_FIGEXP M_FIG C_FIG