Cerebral Amyloid Angiopathy Increases Susceptibility to Infarction After Focal Cerebral Ischemia in Tg2576 Mice

Abstract

We and others have shown that soluble amyloid-β peptide (Aβ) and cerebral amyloid angiopathy (CAA) cause significant cerebrovascular dysfunction in mutant amyloid precursor protein (APP) mice, and that these deficits are greater in aged APP mice having CAA compared to young APP mice lacking CAA. Aβ in young APP mice also increases infarction following focal cerebral ischemia, but the impact of CAA on ischemic brain injury is unknown. To determine this, we assessed cerebrovascular reactivity, cerebral blood flow (CBF), and extent of infarction and neurological deficits following transient middle cerebral artery occlusion (MCAO) in aged APP mice having extensive CAA versus young APP mice lacking CAA (and aged-matched littermate controls). We found that aged APP mice have more severe cerebrovascular dysfunction that is CAA-dependent, have greater CBF compromise during and immediately following MCAO, and develop larger infarctions after MCAO. These data indicate CAA induces a more severe form of cerebrovascular dysfunction than Aβ alone, leading to intra- and post-ischemic CBF deficits that ultimately exacerbate cerebral infarction. Our results shed mechanistic light on human studies identifying CAA as an independent risk factor for ischemic brain injury.

Central vascular disease and exacerbated pathology in a mixed model of type 2 diabetes and Alzheimer's disease

“…These observations might also relate to recent discussion about amyloid-dependent and amyloid-independent stages of AD, with an initial phase consisting of disruption of the neuropil, loss of dendritic spines, remodeling of neurites, and inflammatory responses as a consequence of soluble oligomeric and fibrilar A␤ accumulation, followed by a second phase that would consist of the further development of tangles, and synaptic and neuronal loss (Hyman, 2011). However we can not exclude that amyloid, deposited in leptomeningeal vessels as cerebral amyloid angiopathy (CAA) could induce a more severe form of cerebrovascular dysfunction than A␤ alone in AD mice, as previously suggested (Milner et al, 2014). Also, in humans memory impairment strongly correlates with cortical levels of soluble A␤ species, which include oligomers (Walsh and Selkoe, 2004); in fact, reduction of A␤ levels in AD patients may slow down cognitive decline (Hock et al, 2003).…”

Ischemic brain injury in cerebral amyloid angiopathy

“…One intuitive explanation is that CAA heightens the susceptibility to cerebral infarction via its deleterious effects on vessel architecture and vessel function. 39,83 Advanced amyloid deposition in the vessel wall may cause impaired autoregulation, endothelial dysfunction, blood-brain barrier disruption, thickening of the vessel wall, or even vessel occlusion, thereby inducing hypoperfusion and ischemia around the amyloid-laden vessels. 15,57,83,84 Support for this notion comes from experimental studies in mouse models of CAA, demonstrating decreased vascular reactivity in response to physiologic or pharmacologic stimuli compared with wild-type mice.…”

“…39,83 Advanced amyloid deposition in the vessel wall may cause impaired autoregulation, endothelial dysfunction, blood-brain barrier disruption, thickening of the vessel wall, or even vessel occlusion, thereby inducing hypoperfusion and ischemia around the amyloid-laden vessels. 15,57,83,84 Support for this notion comes from experimental studies in mouse models of CAA, demonstrating decreased vascular reactivity in response to physiologic or pharmacologic stimuli compared with wild-type mice. 83,[85][86][87] Furthermore, mice with CAA showed increased susceptibility to induced ischemia, reflected by lower cerebral blood flow and increased infarct volume after middle cerebral artery occlusion.…”

“…83,[85][86][87] Furthermore, mice with CAA showed increased susceptibility to induced ischemia, reflected by lower cerebral blood flow and increased infarct volume after middle cerebral artery occlusion. 83 It is not clear how well these animal models translate to the human disease, but the finding of impaired vascular reactivity in CAA is consistent with patient studies using functional transcranial Doppler 88 and functional MRI (fMRI). 89,90 Both methods estimate the increase in local blood flow in response to a stimulus.…”

The effect of <italic>Scutellaria baicalensis</italic> stem-leaf flavonoids on spatial learning and memory in chronic cerebral ischemia-induced vascular dementia of rats

“…In addition to the direct interference with the generation and assembly of Aβ peptides into neurotoxic oligomeric aggregates or regulation of prosurvival transcription factors in the brain [12][13][14][15], flavonoids encourage beneficial effects on the vascular system [16]. It has been noticed for decades that cerebral amyloid angiopathy in AD induces a severe form of cerebrovascular dysfunction, leading to intra-and postischemic cerebral blood flow deficits that ultimately exacerbate cerebral infarction [17]. Brain infarcts by themselves had little effect on cognitive status [18]; however, infarcts as well as vascular risk factors and cerebrovascular disease may accelerate Aβ production/aggregation/deposition and contribute to the pathology and symptomatology of AD [19].…”