Cerebral amyloid angiopathy aggravates perivascular clearance impairment in an Alzheimer's disease mouse model

Abstract

Cerebral amyloid angiopathy (CAA), defined as the accumulation of amyloid-beta (Aβ) on the vascular wall, is a major pathology of Alzheimer’s disease (AD) and has been thought to be caused by the failure of Aβ clearance. Although two types of perivascular clearance mechanisms, intramural periarterial drainage (IPAD) and the perivascular cerebrospinal fluid (CSF) influx, have been identified, the exact contribution of CAA on perivascular clearance is still not well understood. In this study, we investigated the effect of CAA on the structure and function of perivascular clearance systems in the APP/PS1 transgenic mouse model. To investigate the pathological changes accompanied by CAA progression, the key elements of perivascular clearance such as the perivascular basement membrane, vascular smooth muscle cells (vSMCs), and vascular pulsation were evaluated in middle-aged (7–9 months) and old-aged (19–21 months) mice using in vivo imaging and immunofluorescence staining. Changes in IPAD and perivascular CSF influx were identified by ex vivo fluorescence imaging after dextran injection into the parenchyma or cisterna magna. Amyloid deposition on the vascular wall disrupted the integrity and morphology of the arterial basement membrane. With CAA progression, vascular pulsation was augmented, and conversely, vSMC coverage was decreased. These pathological changes were more pronounced in the surface arteries with earlier amyloid accumulation than in penetrating arteries. IPAD and perivascular CSF influx were impaired in the middle-aged APP/PS1 mice and further aggravated in old age, showing severely impaired tracer influx and efflux patterns. Reduced clearance was also observed in old wild-type mice without changing the tracer distribution pattern in the influx and efflux pathway. These findings suggest that CAA is not merely a consequence of perivascular clearance impairment, but rather a contributor to this process, causing changes in arterial function and structure and increasing AD severity.