The Role of Smooth Muscle Cell-Specific Nudt21 Depletion in Cerebrovascular Remodeling in Alzheimer's Disease

Yuqing Cai, MEd (Advisor: Harry Karmouty-Quintana, PhD)

          Cerebrovascular remodeling commonly coexists with Alzheimer's disease (AD), yet the mechanisms by which vascular dysfunction contribute to AD progression remain unclear. One potential mechanism linking vascular dysfunction and AD is reduced expression of Nudix hydrolase 21 (Nudt21). In the present study, we investigated whether smooth muscle cell (SMC)-specific Nudt21 depletion promotes cerebrovascular remodeling and whether these vascular changes exacerbate AD-related pathology. Our results demonstrated that SMC-specific Nudt21 depletion led to inward cerebrovascular remodeling, characterized by increased vessel wall thickness, reduced lumen diameter, and an elevated SMA area-to-lumen diameter ratio. In heterozygous Tg-SwDI mice, Nudt21 depletion exacerbated hippocampal Aβ accumulation and reduced locomotor activity. Moreover, our findings suggest that cerebrovascular remodeling may influence locomotor activity through both direct effects of vascular structural changes and indirect effects mediated by increased Aβ burden. Collectively, these findings support an active role for vascular smooth muscle cells in AD progression and identify Nudt21 as a promising upstream regulator linking vascular remodeling and AD pathology, highlighting it as a potential therapeutic target for future interventions.

Advisory Committee:

• Harry Karmouty-Quintana, PhD, Chair
• Callie Kwartler, PhD
• Sean Marrelli, PhD
• Tingting Mills, PhD
• Rodrigo Morales, PhD

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