Abstract
Several large population based or clinical trial studies have suggested that certain dihydropyridine (DHP) L-type calcium channel blockers (CCBs) used for the treatment of hypertension may confer protection against the development of Alzheimer’s disease (AD). However, other studies with drugs of the same class have shown no beneficial clinical effects. In order to determine whether certain DHPs are able to impact underlying disease processes in AD (specifically the accumulation of the Alzheimer’s Aβ peptide), we investigated the effect of several antihypertensive DHPs and non-DHP CCBs on Aβ production. Among the antihypertensive DHPs tested, a few, including nilvadipine, nitrendipine and amlodipine inhibited Aβ production in vitro whereas others had no effect or raised Aβ levels. In vivo, nilvadipine and nitrendipine acutely reduced brain Aβ levels in a transgenic mouse model of AD (Tg PS1/APPsw) and improved Aβ clearance across the blood-brain barrier (BBB) whereas amlodipine and nifedipine were ineffective showing that the Aβ lowering activity of the DHPs is independent of their antihypertensive activity. Chronic oral treatment with nilvadipine decreased Aβ burden in the brains of Tg APPsw (Tg2576) and Tg PS1/APPsw mice and also improved learning abilities and spatial memory. Our data suggest that the clinical benefit conferred by certain antihypertensive DHPs against AD is unrelated to their antihypertensive activity but rely on their ability to lower brain Aβ accumulation by affecting both Aβ production and Aβ clearance across the BBB.
Paris D, Bachmeier C, Patel N, Quadros A, Volmar CH, Laporte V, Ganey J, Beaulieu-Abdelahad D, Ait-Ghezala G, Crawford F, Mullan MJ.
Mol Med. 2010 Dec 17. [Epub ahead of print]
Share on Facebook
Comments Off
Dr. Bachmeier and Dr. Paris recently published an article in Cytotechnology entitled “Characterization and Use of Human Brain Microvascular Endothelial Cells to Examine β-amyloid Exchange in the Blood-Brain Barrier”. They are currently using this model of the BBB to elucidate the mechanisms responsible for the removal of β-amyloid from the brain. In addition, this model is being used as a screen to identify molecules that facilitate β-amyloid clearance across the BBB with the goal of discovering a new class of therapies for the treatment of Alzheimer’s disease.
Abstract Alzheimer’s disease (AD) is characterized by excessive cerebrovascular deposition of the β-amyloid peptide (Aβ). The investigation of Aβ transport across the blood-brain barrier (BBB) has been hindered by inherent limitations in the cellular systems currently used to model the BBB, such as insufficient barrier properties and poor reproducibility. In addition, many of the existing models are not of human or brain origin and are often arduous to establish and maintain. Thus, we characterized an in vitro model of the BBB employing human brain microvascular endothelial cells (HBMEC) and evaluated its utility to investigate Aβ exchange at the blood-brain interface. Our HBMEC model offers an ease of culture compared with primary isolated or coculture BBB models and is more representative of the human brain endothelium than many of the cell lines currently used to study the BBB. In our studies, the HBMEC model exhibited barrier properties comparable to existing BBB models as evidenced by the restricted permeability of a known paracellular marker. In addition, using a simple and rapid fluormetric assay, we showed that antagonism of key Aβ transport proteins significantly altered the bi-directional transcytosis of fluorescein-Aβ (1-42) across the HBMEC model. Moreover, the magnitude of these effects was consistent with reports in the literature using the same ligands in existing in vitro models of the BBB. These studies establish the HBMEC as a representative in vitro model of the BBB and offer a rapid fluorometric method of assessing Aβ exchange between the periphery and the brain.
Share on Facebook
Comments Off
Scott Ferguson will be presenting the paper on Friday (12/10/2010) at 4:00 PM in Roskamp Institute.
Title: A Bacterium That Can Grow by Using Arsenic Instead of Phosphorus
www.sciencexpress.org / 2 December 2010 / Page 1 / 10.1126/science.1197258
Journal Club is held every Friday. For change in schedule please check our Twitter account or Facebook page.
The Roskamp Institute is devoted to understanding causes and finding cures for neuropsychiatric and neurodegenerative disorders and addictions. The Institute utilizes a broad range of scientific approaches to understanding the causes of and potential therapies for these disorders with an emphasis on Alzheimer’s disease. For more information, please call (941)752-2949
Share on Facebook
Comments Off