Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein

Abstract

The amyloid-beta (A beta) peptide, which is derived from the amyloid precursor protein (APP), is involved in the pathogenesis of Alzheimer's dementia and impairs endothelium-dependent vasodilation in cerebral vessels. We investigated whether cerebrovascular autoregulation, i.e., the ability of the cerebral circulation to maintain flow in the face of changes in mean arterial pressure (MAP), is impaired in transgenic mice that overexpress APP and A beta. Neocortical cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized APP(+) and APP(-) mice. MAP was elevated by intravenous infusion of phenylephrine and reduced by controlled exsanguination. In APP(-) mice, autoregulation was preserved. However, in APP(+) mice, autoregulation was markedly disrupted. The magnitude of the disruption was linearly related to brain A beta concentration. The failure of autoregulation was paralleled by impairment of the CBF response to endothelium-dependent vasodilators. Thus A beta disrupts a critical homeostatic mechanism of the cerebral circulation and renders CBF highly dependent on MAP. The resulting alterations in cerebral perfusion may play a role in the brain dysfunction and periventricular white-matter changes associated with Alzheimer's dementia.

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.…”

“…Reduction in cerebral blood flow precedes the development of dementia in AD 52 and occurs well before any behavioral or pathological abnormalities in animal models of the disease 24, 39. We still have only a limited understanding of the pathogenesis.…”

“…In animal studies, Aβ peptides reduced cerebral blood flow, interfered with cerebral autoregulation and impeded functional hyperaemia 39, 40, 41. We previously demonstrated an increase in the level of the vasoconstrictor peptide endothelin‐1 (EDN1) in the cerebral cortex in AD 46.…”

Assessing White Matter Ischemic Damage in Dementia Patients by Measurement of Myelin Proteins

“…[2][3][4][5] The mechanisms underlying alterations in the white matter in AD, and their relationship to other aspects of AD pathology, are unclear. There is a possible interdependence between ischemia and amyloid-b (Ab) in AD: ischemia has been shown to increase Ab production by upregulation of BACE1, 6,7 and by reduced vascular clearance and enzymatic degradation, 8 whereas increased Ab may enhance ischemia by vasoconstriction, impairment of cerebral autoregulation, and functional hyperemia, [9][10][11][12] and through deposition in the walls of blood vessels to cause CAA. 13,14 Current methods for post-mortem assessment of ante-mortem ischemic change in the white matter are varied and subjective.…”

Functional magnetic resonance imaging as a dynamic candidate biomarker for Alzheimer's disease

“…Colocalized with sites of greatest amounts of neurodegeneration, the basement membrane of capillaries in the cerebral cortex of AD patients is prominently thickened, mostly due to increased collagen deposition (Mancardi et al, 1980) and deposition of amorph Aβ fibrils (reviewed in Farkas and Luiten, 2001). Beside these pathological alterations associated with insoluble fibrillar Aβ, experimental administration of soluble Aβ monomers in experimental settings consistently showed massive abolishment of functional cerebrovascular autoregulation, reduced functial hyperemia and caused a fundamental shift of vascular reactivity in favour of vasconstricting stimuli, even in the absence of fibrillar plaque deposits (Crawford et al, 1998;Niwa et al, 2000;Niwa et al, 2001;Niwa et al, 2002;Park et al, 2004).…”