Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice

Abstract

Cerebrovascular lesions related to congophilic amyloid angiopathy (CAA) often accompany deposition of β-amyloid (Aβ) in Alzheimer’s disease (AD), leading to disturbed cerebral blood flow and cognitive dysfunction, posing the question how cerebrovascular pathology contributes to the pathology of AD. To address this question, we characterised the morphology, biochemistry and functionality of brain blood vessels in transgenic arctic β-amyloid (arcAβ) mice expressing human amyloid precursor protein (APP) with both the familial AD-causing Swedish and Arctic mutations; these mice are characterised by strong CAA pathology. Mice were analysed at early, mid and late-stage pathology. Expression of the glucose transporter GLUT1 at the blood–brain barrier (BBB) was significantly decreased and paralleled by impaired in vivo blood-to-brain glucose transport and reduced cerebral lactate release during neuronal activation from mid-stage pathology onwards. Reductions in astrocytic GLUT1 and lactate transporters, as well as retraction of astrocyte endfeet and swelling consistent with neurovascular uncoupling, preceded wide-spread β-amyloid plaque pathology. We show that CAA at later disease stages is accompanied by severe morphological alterations of brain blood vessels including stenoses, BBB leakages and the loss of vascular smooth muscle cells (SMCs). Together, our data establish that cerebrovascular and astrocytic pathology are paralleled by impaired cerebral metabolism in arcAβ mice, and that astrocyte alterations occur already at premature stages of pathology, suggesting that astrocyte dysfunction can contribute to early behavioural and cognitive impairments seen in these mice.

Astrocytic transporters in Alzheimer's disease

“…The molecular mechanisms behind this are poorly understood, although human AD studies highlight that astrocyte/endothelial GLUT1 (as well as neuronal GLUT3) levels are reduced in post-mortem AD brains (99,100). Loss of astrocyte glucose transporters (GLUT1) is also found in the arcAβ (expressing both the Swedish and Arctic APP mutations) transgenic animal model, with no detectable changes in neuronal glucose transporters (97).…”

“…Perturbed glucose metabolism is a contributing factor to the pathogenesis of AD (97,101,102). This disruption is reported to be one of the earliest features of AD, in that a reduction in brain glucose metabolism can be detected (103) and is used as a diagnostic tool (104).…”

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…It has been shown that astrocyte changes precede widespread amyloid pathology and BBB disruption in a mouse model that develops plaques and CAA. 165 This suggests that Ab-induced astrocyte changes in AD may contribute to BBB dysfunction, but the mechanisms by which this occurs have yet to be determined.blood-brain barrier in Alzheimer's disease MA Erickson et al …”

Brain Energy Metabolism in Health and Disease

“…Aggregate forms of amyloid can modify glucose metabolism and oxidative stress in astrocytes, affecting neuronal cells and probably contributing to neuronal death (Allaman et al, 2010). Indeed, reduction of GLUT1 and MCT expression, as well as the retraction of of astrocyte endfeet occurs in Alzheimer's disease producing uncoupling of the neurovascular unit (Merlini et al, 2011). The activity of PPP is increased in Alzheimer's disease.…”

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