Age-Dependent Neurovascular Dysfunction and Damage in a Mouse Model of Cerebral Amyloid Angiopathy

Abstract

Background and Purpose Accumulation of amyloid-β in cerebral blood vessels occurs in familial and sporadic forms of cerebral amyloid angiopathy and is a prominent feature of Alzheimer disease. However, the functional correlates of the vascular pathology induced by cerebral amyloid angiopathy and the mechanisms involved have not been fully established. Methods We used male transgenic mice expressing the Swedish, Iowa, and Dutch mutations of the amyloid precursor protein (Tg-SwDI) to examine the effect of cerebral amyloid angiopathy on cerebrovascular structure and function. Somatosensory cortex cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized Tg-SwDI mice and wild-type littermates equipped with a cranial window. Results Tg-SwDI mice exhibited reductions in cerebral blood flow responses to whisker stimulation, endothelium-dependent vasodilators, or hypercapnia at 3 months when compared with wild-type mice, whereas the response to adenosine was not attenuated. However, at 18 and 24 months, all cerebrovascular responses were markedly reduced. At this time, there was evidence of cerebrovascular amyloid deposition, smooth muscle fragmentation, and pericyte loss. Neocortical superfusion with the free radical scavenger manganic(I–II)meso-tetrakis(4-benzoic acid) porphyrin rescued endothelium-dependent responses and functional hyperemia completely at 3 months but only partially at 18 months. Conclusions Tg-SwDI mice exhibit a profound age-dependent cerebrovascular dysfunction, involving multiple regulatory mechanisms. Early in the disease process, oxidative stress is responsible for most of the vascular dysfunction, but with advancing disease structural alterations of the vasomotor apparatus also play a role. Early therapeutic interventions are likely to have the best chance to counteract the deleterious vascular effects of cerebral amyloid angiopathy.

Chronic Hypertension Leads to Neurodegeneration in the TgSwDI Mouse Model of Alzheimer’s Disease

“…It is possible that the deposition of microvascular Aβ compromises the survival of NVU cells such as pericytes and endothelial cells. Although others have shown pericyte loss in TgSwDI mice at 18 months-of-age 12 , we found that chronic hypertension induced pericyte loss significantly earlier (9–10 months-of-age; Figure 5G–L). Furthermore, neuronal loss has never been reported in this transgenic model, yet hypertensive TgSwDI mice demonstrated significant neurodegeneration in a subregion of the hippocampus (Figure 5A–F).…”

“…Perictye loss occurs in severely affected AD patients 33 and in older TgSwDI mice 12 , so we examined levels of PDGFRβ to determine if the expression of this pericyte marker is altered in our hypertensive groups. After 6 months of L-NAME treatment, hypertensive TgSwDI mice exhibited a significant decrease in PDGFRβ staining in both the DG and DS (Figure 5G,J vs H,K; I,L).…”

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

“…The elevated production of EDN1 may be an unfortunate side effect of over‐activation of this pathway by excessive Aβ42. In contrast, endothelial production of EDN1, mediated by ECE1 and driven by Aβ40, is more likely to contribute to episodic, free radical‐dependent dysfunction of vascular regulation in AD 48 (Figure 7), including abnormalities of autoregulation and functional hyperaemia demonstrated initially in mouse models of cerebral Aβ accumulation 24, 39 and CAA 49, 54, and more recently in patients with AD 14 and probable CAA 50. It should be noted, in addition, that EDN1 is very unlikely to be the sole nonstructural mediator of hypoperfusion of the precuneus in early AD.…”

Vascular and Metabolic Factors in Alzheimer’s Disease and Related Dementias: Introduction

“…The cerebrovascular effects of Aβ are mediated in large part by activation of the free radical-producing enzyme NADPH oxidase through the innate immunity receptor CD36, and are reversible by pharmacological or genetic approaches to scavenge radicals or block their production (Han et al, 2015; Iadecola et al, 1999; Nicolakakis et al, 2008; Park et al, 2013; 2008). However, these neurovascular alterations become irreversible in advanced disease, due to accumulation of Aβ in cerebral blood vessels which leads to damage to endothelium, smooth muscle cells and pericytes (Park et al, 2013; 2014). Collectively, the evidence to date suggests that Aβ, in addition to its well-established effects on synaptic function, also targets cerebral blood vessels leading to neurovascular dysfunction and lowering the threshold for cerebral ischemic injury.…”