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. We conducted bulk mRNA-seq to investigate the transcriptomic changes associated with cerebral amyloid angiopathy (CAA) in Tg-SwDI mice compared to wild-type mice and to evaluate the effect of 4F treatment in Tg-SwDI mice. RNA-Seq data were collected from the brains of 15 mice (8 males and 7 females) following 12 weeks of daily 4F or vehicle treatment. Sequencing was performed using the Illumina NovaSeq 6000 platform, generating 20 million reads per sample on a 150-bp paired-end run.

阿尔茨海默病（Alzheimer's disease, AD）是全球范围内最常见的年龄相关性痴呆病因，目前有效治疗手段十分有限。脑淀粉样血管病（cerebral amyloid angiopathy, CAA）是AD的关键病理标志之一，以脑血管壁内β淀粉样蛋白（amyloid-β, Aβ）沉积为特征，与脑出血、脑血管功能障碍及认知损害密切相关。此外，CAA被认为是抗Aβ免疫治疗的主要不良反应——淀粉样蛋白相关成像异常（amyloid-related imaging abnormalities, ARIA）的潜在发病基础。

临床与动物研究的大量证据表明，高密度脂蛋白（high-density lipoprotein, HDL）及其主要蛋白组分载脂蛋白（apolipoprotein, APO）A-I水平升高，与CAA负荷降低及认知功能改善显著相关。4F是一种APOA-I/HDL模拟肽，目前已进入心血管疾病的临床试验阶段。

本研究旨在探究HDL模拟肽4F能否在已成熟构建的CAA/AD转基因Tg-SwDI小鼠模型中，调控CAA进展及相关认知缺陷与神经病理改变。将年龄与性别匹配的Tg-SwDI小鼠分为两组，每日分别通过腹腔注射给予4F或赋形剂（磷酸盐缓冲液, PBS），持续干预12周。

结果显示，4F治疗可降低CAA负荷及整体Aβ斑块沉积，并减轻CAA相关的小胶质细胞增生。无偏倚脑转录组分析揭示，SwDI小鼠大脑存在显著炎症状态，而4F治疗可逆转血管细胞（尤其是血管平滑肌细胞）的过度激活，缓解CAA/AD小鼠的脑血管炎症。

本研究为4F在减轻AD中CAA及其相关致病过程（包括ARIA）方面的治疗潜力提供了实验依据。本研究通过批量mRNA测序（bulk mRNA-seq），旨在探究Tg-SwDI小鼠相较于野生型小鼠的脑淀粉样血管病相关转录组变化，并评估4F治疗对Tg-SwDI小鼠的干预效果。

研究共采集15只小鼠（8只雄性、7只雌性）的脑组织RNA样本，这些小鼠均接受了12周的每日4F或赋形剂治疗。测序采用Illumina NovaSeq 6000测序平台完成，每个样本在150bp双端测序模式下生成约2000万条测序读段。