Caffeine protects against disruptions of the blood-brain barrier in animal models of Alzheimer's and Parkinson's diseases

Abstract

Sporadic Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common neurodegenerative diseases and as such they represent major public health problems. Finding effective treatments for AD and PD represents an unmet and elusive goal largely because these diseases are chronic and progressive, and have a complicated and ill-understood pathogenesis. Although the underlying mechanisms are not fully understood, caffeine, the most commonly ingested psychoactive drug in the world, has been shown in human and animal studies to be protective against AD and PD. One mechanism implicated in the pathogenesis of AD and PD is blood-brain barrier (BBB) dysfunction and we reported recently that caffeine exerts protective effects against AD and PD at least in part by keeping the BBB intact. The present review focuses on the role of BBB dysfunction in the pathogenesis of AD and PD, caffeine's protective effects against AD and PD, and potential mechanisms whereby caffeine protects against BBB leakage.

Figure 1

A schematic diagram of endothelial cells that form the blood–brain barrier (BBB) and their associations with the lumen of a blood vessel, pericytes, basement membrane and endfeet of astrocytes. The restrictive nature of the BBB is due to tight junctions between adjacent endothelial cells at the apical membrane and a continuous basement membrane underlying the endothelium. Tight junctions consist of three transmembrane proteins occludin, claudins, and junction adhesion molecules (JAM) as well as a number of membrane-associated and accessory proteins including zonula occludens (ZO-1).

Figure 2

In a rabbit model of sporadic AD, caffeine at a dose of 3 mg/day blocked cholesterol-enriched diet-induced increases in leakage of Evan’s blue dye (A) and decreases in occludin immunostaining (B) and protein levels (C) in olfactory bulb (Bar = 100 μm). Modified with permission from Ref [96]. In a MPTP neurotoxin model of PD, caffeine at the dose of 10 mg/kg/day blocked MPTP-induced increases in leakage of Evan’s blue dye (D) and decreases in occludin immunostaining (E) and protein levels (F) in striatum (Bar = 20 μm). Modified with permission from Ref [177].