The HDL-Mimetic Peptide 4F Mitigates Vascular and Cortical Amyloid Pathology and Associated Neuroinflammation in a Transgenic Mouse Model of Cerebral Amyloid Angiopathy and Alzheimer's Disease

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite recent advances, more effective and safer treatment options for AD are needed. Cerebral amyloid angiopathy (CAA) is one of the key pathological hallmarks of AD characterized by amyloid-β (Aβ) deposition in the cerebral vasculature and is associated with intracerebral hemorrhage, cerebrovascular dysfunction, and cognitive impairment. CAA is also considered to underlie the main adverse effect of recently FDA-approved anti-Aβ immunotherapies, namely the amyloid-related imaging abnormalities (ARIA). Substantial evidence has shown that elevated levels of high-density lipoprotein (HDL) and its main protein component, APOA-I, are associated with reduced CAA and superior cognitive function. 4F is an APOA-I/HDL-mimetic peptide and its clinical safety and activity have been demonstrated in human trials for cardiovascular diseases. The present study investigates whether treatment with 4F modulates CAA and associated cognitive deficits and neuropathologies in the well-established Tg-SwDI mouse model of CAA/AD. Age/sex-matched Tg-SwDI mice received daily treatments of 4F or vehicle (PBS), respectively, by intraperitoneal injections for 12 weeks. The results showed that 4F treatment reduced overall Aβ plaque deposition and CAA, and attenuated CAA-associated microgliosis, without significantly affecting total levels of Aβ, astrocytosis, and behavioral function. Unbiased transcriptomic analysis revealed a heightened inflammatory state in the brain of SwDI mice and that 4F treatment reversed the overactivation of vascular cells, in particular vascular smooth muscle cells, relieving cerebrovascular inflammation in CAA/AD mice. Our study provides experimental evidence for the therapeutic potential of 4F to mitigate CAA and associated pathologies in AD.