Neurovascular function in Alzheimer's disease patients and experimental models

Abstract

The ability of the brain to locally augment glucose delivery and blood flow during neuronal activation, termed neurometabolic and neurovascular coupling, respectively, is compromised in Alzheimer's disease (AD). Since perfusion deficits may hasten clinical deterioration and have been correlated with negative treatment outcome, strategies to improve the cerebral circulation should form an integral element of AD therapeutic efforts. These efforts have yielded several experimental models, some of which constitute AD models proper, others which specifically recapture the AD cerebrovascular pathology, characterized by anatomical alterations in brain vessel structure, as well as molecular changes within vascular smooth muscle cells and endothelial cells forming the blood-brain barrier. The following paper will present the elements of AD neurovascular dysfunction and review the in vitro and in vivo model systems that have served to deepen our understanding of it. It will also critically evaluate selected groups of compounds, the FDA-approved cholinesterase inhibitors and thiazolidinediones, for their ability to correct neurovascular dysfunction in AD patients and models. These and several others are emerging as compounds with pleiotropic actions that may positively impact dysfunctional cerebrovascular, glial, and neuronal networks in AD.

Figures

Figure 1

The concept of brain deactivation in Alzheimer's disease (AD). The ability to deactivate task-irrelevant auditory cortices during active spatial navigation was decreased in subjects with mild cognitive impairment (MCI), and to a greater extent, in those with AD. Altered regional cerebral blood flow (CBF) patterns were measured with O15-positron emission tomography (PET). Reproduced from Drzezga et al (2005).

Figure 2

The role of soluble and insoluble Aβ in cerebrovascular dysfunction of amyloid precursor protein (APP) mice. (A) The cerebral blood flow (CBF) increase to whisker stimulation is impaired in 3- to 4-month-old Tg2576 mice lacking Aβ deposits, and more so in 12-month-old Tg2576 animals, as assessed through open cranial window and laser Doppler flowmetry (LDF). Deficits were absent in Tg2576 mice missing the Nox2 catalytic NADPH oxidase subunit. This implicates soluble Aβ-induced oxidative stress in the dysfunctions. White bars, 4 months old; Black bars, 12 months old; WT, wild type; *, different from WT; #, different from young Tg2576 mice. Reproduced from Park et al (2008) by The National Academy of Sciences of the USA. (B) Hypercapnia-induced dilatation is impaired in 6-month-old Tg2576 mice lacking cerebral amyloid angiopathy (CAA), and further impaired in 12- to 15-month-old animals with increasing CAA severity and smooth muscle cell disarrangement, the latter illustrated and quantified in panels (a–e). CAA: methoxy-X04 stained blue; smooth muscle cells: phalloidin stained green. Scale bars: left, 50 μm; right, 20 μm. Reproduced from Han et al (2008) with permission conveyed through Copyright Clearance Center, Inc. (C) Reduced cerebrovascular responsiveness in the proximal CAA-free segment of the middle cerebral artery (MCA) (delineated by arrowheads, with first, second, and third subsegments magnified in the three panels) suggests effects of soluble Aβ in a 12-month-old J20 APP mouse. Scale bars: left, 0.5 cm; right, 0.2 cm. ACA, anterior cerebral artery; ICA, internal carotid artery; PComA, posterior communicating artery; PCA, posterior cerebral artery. Reprinted from Tong et al (2009) with permission from Elsevier.

Figure 3

Functional hyperemic rescue by Tempol in 7.5-month-old J20 amyloid precursor protein (APP) mice. (A) The neurovascular coupling response to whisker stimulation was improved in all APP mice tested before and after 10-day in vivo therapy with the antioxidant Tempol (1 mmol/L in drinking water, Sigma-Aldrich, St Louis, MO, USA), as measured with laser Doppler flowmetry (LDF), following the same protocols as in Nicolakakis et al (2008) (n=5, paired Student's t-test, GraphPad Prism 4, San Diego, CA, USA). (B) Responses of wild-type (WT) mice were mostly unaffected by treatment (n=4, paired Student's t-test). (C) Short Tempol therapy completely normalized the impaired CBF response of APP mice (gray bars, n=5) to that of WT littermates (white bars, n=4) (***P<0.001 for difference to all other groups, two-way analysis of variance with Newman–Keuls post hoc multiple comparison test (Statistica 9, StatSoft, Tulsa, OK, USA)). Error bars represent s.e.m. Results are expressed as the percent cerebral blood flow (CBF) increase during whisker stimulation relative to prestimulation baseline.

Figure 4

Alzheimer's disease (AD) neurovascular dysfunction and chronic hypoperfusion are associated with diseased neuronal, astrocytic, and vascular networks. Countering neurovascular impairment with peroxisome proliferator-activated receptor γ (PPARγ) agonists, acetylcholinesterase inhibitors (AChEi), or other compounds may improve clinical outcome and delay progression to severe dementia. CAA, cerebral amyloid angiopathy; TGF-β1, transforming growth factor-β 1.