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Vascular smooth muscle cell dysfunction contribute to neuroinflammation and Tau hyperphosphorylation in Alzheimer
Jorge A Aguilar-Pineda1, Karin J Vera-Lopez1, Pallavi Shrivastava1
1Laboratory of Genomics and Neurovascular Diseases, Vicerrectorado de investigacion, Universidad Catolica de Santa Maria, Arequipa, Peru.
Abstract:
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.
Insights
Vascular smooth muscle cells (VSMCs) in Alzheimer disease (AD) brains lose contractile markers and become pro-inflammatory, correlating with Tau pathology. This suggests VSMC dysfunction contributes to AD and offers a therapeutic target.
Area of Science:
- Neuroscience
- Vascular Biology
- Pathology
Background:
- Emerging evidence links vascular factors to neurodegenerative diseases.
- The specific role of vascular smooth muscle cells (VSMCs) in Alzheimer disease (AD) pathogenesis remains unclear.
Purpose of the Study:
- To investigate the role and characteristics of VSMCs in Alzheimer disease (AD).
- To explore VSMC phenotypic changes and their correlation with AD pathology markers.
Main Methods:
- Analysis of VSMCs from human AD brains and AD animal models.
- Ex vivo and in vitro experiments to assess VSMC behavior under AD-like conditions.
- Immunohistochemistry and protein expression analysis (Sm22α, CD68, Tau).
Main Results:
- VSMCs in AD brains exhibit deficiency in contractile markers and adopt pro-inflammatory phenotypes.
- VSMC changes correlate with Tau accumulation and hyperphosphorylation (Y18, T205, S262).
- VSMC dysfunction is age-dependent and inversely correlated with Tau and CD68 expression in mouse models.
Conclusions:
- Dysfunctional VSMCs contribute significantly to Alzheimer disease (AD) pathogenesis.
- VSMCs represent a potential therapeutic target for AD treatment.
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