Biochemical Abnormalities of the Blood-Brain Barrier in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive degenerative disorder characterized by widespread functional disturbances of human brain involving loss of memory reasoning and judgement. The role of the cerebral circulation in the pathogenesis of this disorder has not been well delineated, although both structural and functional abnormalities of the blood-brain barrier (BBB) in AD have been documented. Our laboratory has previously shown that important biochemical functions of the BBB are modulated by adrenergic receptors (J. Neurochem. 4–4:1732, 1985). The purpose of this study was to examine whether adrenergic control of BBB function, at the level of adrenergic receptors, is altered in AD. Cerebral microvessels were isolated from autopsy material from AD patients and non-demented elderly controls by a modification of our procedure for rat microvessel isolation. Alpha and β-adrenergic receptors were characterized using the specific antagonists [3H] prazosin (PZ) and 125I-iodocyanopindolol (ICYP), respectively. Examination of PZ binding indicated a significant (P < 0.001) decrease in α-receptor binding at each ligand concentration (0.05 – 0.3nM) and a two-fold decrease in maximum binding capacity [Bmax in microvessels from AD patients with no change in receptor affinity (KD)]. Interestingly, β-adrenergic receptor binding parameters (Bmax and KD) were comparable in control and AD microvessels. These data demonstrate a selective decrease in α-adrenergic receptors in cerebral microvessels in AD and suggest that this abnormality may alter BBB functions, such as permeability, that are thought to be modulated by α-receptors. Thus, this in vitro preparation can be used to unravel the biochemical basis of cerebral endothelial cell dysfunction in AD that may contribute to the multistep pathogenesis of cell death in AD. [Supported in part by a grant from the American Health Assistance Foundation (PG) and the Atkinson Charitable Foundation of Toronto (MJB)].