Abstract

Introduction: 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. Methods: We crossed the Familial Danish Dementia mouse model (Tg-FDD), which develops vascular amyloid, with tau-null (mTau-/-) mice to generate a CAA model lacking endogenous tau (Tg-FDD/mTau-/-). Behavioral, electrophysiological, histological, and transcriptomic analyses were performed. Results: 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. Conclusion: 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. Highlights: 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). Tau reduction decreases astrocytic reactivity, alters neuroinflammatory gene expression, and enhances oligodendrocyte function, suggesting a protective role against neuroinflammation in CAA. 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.