Tau depletion diminishes vascular amyloid‐related deficits in a mouse model of cerebral amyloid angiopathy

<jats:title>Abstract</jats:title><jats:sec><jats:title>INTRODUCTION</jats:title><jats:p>Tau is essential for amyloid beta (Aβ)–induced synaptic and cognitive deficits in Alzheimer's disease (AD), making its downregulation a therapeutic target. Cerebral amyloid angiopathy (CAA), a major vascular contributor to cognitive decline, affects over 90% of patients with AD. This study explores the impact of tau downregulation on CAA pathogenesis.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>We crossed the Familial Danish Dementia mouse model (Tg‐FDD), which develops vascular amyloid, with tau‐null (mTau<jats:sup>−/−</jats:sup>) mice to generate a CAA model lacking endogenous tau (Tg‐FDD/mTau<jats:sup>−/−</jats:sup>). Behavioral, electrophysiological, histological, and transcriptomic analyses were performed.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Tau depletion ameliorated motor and synaptic impairments, reduced vascular amyloid deposition, and prevented vascular damage. Tau ablation also mitigated astrocytic reactivity and neuroinflammation associated with vascular amyloid accumulation.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p>These findings provide the first in vivo evidence of the beneficial effects of tau downregulation in a CAA mouse model, supporting tau reduction as a potential therapeutic strategy for patients with parenchymal and vascular amyloid deposition.</jats:p></jats:sec><jats:sec><jats:title>Highlights</jats:title><jats:p><jats:list list-type="bullet">
<jats:list-item><jats:p>Tau ablation improves motor function and synaptic impair, reduces cerebrovascular amyloid deposits, and prevents vascular damage in a mouse model of cerebral amyloid angiopathy (CAA).</jats:p></jats:list-item>
<jats:list-item><jats:p>Tau reduction decreases astrocytic reactivity, alters neuroinflammatory gene expression, and enhances oligodendrocyte function, suggesting a protective role against neuroinflammation in CAA.</jats:p></jats:list-item>
<jats:list-item><jats:p>These findings highlight tau reduction as a potential therapeutic strategy to mitigate CAA‐induced pathogenesis, with implications for treating patients with both parenchymal and vascular amyloid deposition.</jats:p></jats:list-item>
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