(The) effects of Alzheimer's disease and aging on perivascular clearance

Abstract

Accumulation of Amyloid-beta (Aβ) in blood vessel walls and brain tissues is major pathologies of AD. Aβ depositions on the outer wall of vessels are called cerebral amyloid angiopathy (CAA) and have been thought to be a result of the failure of Aβ clearance. 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. The effect of amyloid deposition on the structure and function of perivascular clearance systems was investigated using the APP/PS1 transgenic mouse model. The pathological changes of the key elements of system such as the periarterial 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 accompanied by CAA progression. Structural and functional changes of vasculature were examined by in vivo imaging and immunofluorescence. CSF influx and interstitial fluid efflux was quantified by ex vivo fluorescence imaging. Amyloid deposition on the vascular wall disrupted the integrity and morphology of the 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. ISF efflux and perivascular CSF influx were impaired in the middle-aged APP/PS1 mice and further aggravated in old age, showing severely impaired patterns. Reduced clearance was also observed in old-aged wild-type mice, however the ISF efflux and CSF influx patterns were not completely destroyed. Solute transport within the brain is significantly decreased with aging, but not in AD. 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.