The Mysterious Link between Cholesterol and Alzheimer?s Disease: Is the Blood-Brain Barrier a Suspect?

Abstract

It is now well accepted that the deposition and aggregation of amyloid β (Aβ) peptides are hallmarks of Alzheimer’s disease (AD) [1]. These peptides are constitutively secreted by neurons but (for reasons that remain to be established) Aβ metabolism is altered in AD patients and leads slowly to the neurodegenerative process. With these considerations in mind, the identification of genetic, biochemical, environmental and dietary factors influencing Aβ peptide synthesis, clearance and degradation became a high priority for researchers working on AD. The enzyme responsible for Aβ peptide synthesis was soon identified as a β-secretase called β-site amyloid precursor protein cleaving enzyme 1 (BACE1) [2]. The most important genetic risk factor for late-onset AD was identified as the APOe4 allele [ 3]. This gene encodes an apolipoprotein, a protein component of the low-density lipoprotein (LDL) particles involved in lipid transport throughout the body; this finding highlighted a probable relationship between AD and cholesterol metabolism. More recently, two other susceptibility loci linked to cholesterol metabolism have been identified in AD: CLU (coding for clusterin, another apolipoprotein) [4] and ABCA7 [5] (coding for the ATP-binding cassette sub-family A member 7 transporter involved in cholesterol homeostasis [6] ). This link between AD and cholesterol metabolism was reinforced by the observation that the sterol can modulate BACE1 activity and promote Aβ peptide biosynthesis [7]. Cholesterol was also identified as dietary risk factor in humans; since elevated serum cholesterol is a risk factor for developing AD and amount of Aβ peptide in the brain correlates with serum levels of LDL and total cholesterol [8,9]. Moreover, rabbits and mice on a cholesterol-enriched diet show elevated serum cholesterol levels, increased Aβ peptide deposition and cognitive impairment [10-14]. However, the reasons why serum cholesterol influences AD are difficult to determine, for two main reasons. Firstly, most of the accretion of cholesterol in the central nervous system (CNS) is due to de novo synthesis (reviewed in [15]). Secondly, the brain is isolated from the rest of body by the blood-brain barrier (BBB), a dynamic interface formed by brain capillary endothelial cells (BCECs) and sealed by complex tight junctions that restrict the paracellular pathway [16]. One of the BBB’s main roles is to supply the brain with essential nutrients and mediate the efflux of many waste products. To this end, BCECs express specific receptors or transporters in their luminal (plasma-side) and/ or abluminal (brain-side) membranes that force molecules to take the transcellular route.