High-fat diet-induced atherosclerosis promotes neurodegeneration in the triple transgenic (3 × Tg) mouse model of Alzheimer’s disease associated with chronic platelet activation

BACKGROUND: Epidemiological studies link vascular disease risk factors such as atherosclerosis, hypertension, and diabetes mellitus with Alzheimer’s disease (AD). Whether there are direct links between these conditions to β-amyloid (Aβ) aggregation and tau pathology is uncertain. METHODS: To investigate the possible link between atherosclerosis and AD pathology, we subjected triple transgenic (3 × Tg) AD mice to a high-fat diet (HFD) at 3 months of age, which corresponds to early adulthood in humans. RESULTS: After 9 months of treatment, HFD-treated 3 × Tg mice exhibited worse memory deficits accompanied by blood hypercoagulation, thrombocytosis, and chronic platelet activation. Procoagulant platelets from HFD-treated 3 × Tg mice actively induced the conversion of soluble Aβ40 into fibrillar Aβ aggregates, associated with increased expression of integrin αIIbβ(3) and clusterin. At 9 months and older, platelet-associated fibrillar Aβ aggregates were observed to obstruct the cerebral blood vessels in HFD-treated 3 × Tg mice. HFD-treated 3 × Tg mice exhibited a greater cerebral amyloid angiopathy (CAA) burden and increased cerebral vascular permeability, as well as more extensive neuroinflammation, tau hyperphosphorylation, and neuron loss. Disaggregation of preexisting platelet micro-clots with humanized GPIIIa49-66 scFv Ab (A11) significantly reduced platelet-associated fibrillar Aβ aggregates in vitro and improved vascular permeability in vivo. CONCLUSIONS: These findings suggest that a major contribution of atherosclerosis to AD pathology is via its effects on blood coagulation and the formation of platelet-mediated Aβ aggregates that compromise cerebral blood flow and therefore neuronal function. This leads to cognitive decline. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-021-00890-9.