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 age-related dementia worldwide with limited effective treatments. 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 anti-Aβ immunotherapies, the amyloid-related imaging abnormalities (ARIA). Substantial evidence from clinical and animal studies has shown that elevated levels of high-density lipoprotein (HDL), and its main protein component, apolipoprotein (APO) A-I, are associated with reduced CAA and superior cognitive function. 4F is an APOA-I/HDL-mimetic peptide that has advanced into clinical trials for cardiovascular diseases. The present study aimed to investigate whether treatment with the HDL mimetic peptide 4F modulates CAA and associated cognitive deficits and neuropathologies in the well-established transgenic Tg-SwDI mouse model of CAA/AD. Age- and sex-matched Tg-SwDI mice received daily treatments of 4F or vehicle (PBS), respectively, by intraperitoneal injections for 12 weeks. The results showed that the 4F treatment reduced CAA as well as overall Aβ plaque deposition, and attenuated microgliosis associated with CAA. Unbiased brain 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 its associated pathogenic processes in AD, including ARIA.