Alzheimer's disease (AD) is a progressive brain disorder affecting as many as 5.1 million Americans (NIH). It is the most prevalent form of senile dementia that destroys brain cells, causing memory loss, decline in mental function and personality changes. Plaques, tangles and loss of connections between nerve cells (neurons) in the brain are the main features of AD. Plaques are believed to be formed from β-amyloid (Aβ) peptides. BACE1 (beta-site amyloid precursor protein cleavage enzyme 1) is the major neuronal beta-secretase involved in the production of Aβ peptides, and hence has been identified as one of the promising therapeutic targets for treating AD. Several companies including Merck, Bristol Myers Squib and, Eli Lily and Company are developing BACE1 inhibitors for this purpose. The use of BACE1 inhibitors however causes severe phenotypic deficiencies in presynaptic function (as shown in the mouse model, Laird et al., 2005 Journal of Neuroscience, Wang et al., 2008 Journal of Neuroscience).

Inventors at the University of Maryland, College Park have for the first time shown alpha7-nicotinic acetylcholine receptor activator with BACE1 inhibitors as a potential treatment for Alzheimer's disease. They recently found that the presynaptic dysfunction in the absence of BACE1 (BACE1 gene knockout or genetically altered mice lacking BACE1) could be alleviated by activation of α7-nicotinic acetylcholine receptors (α7-nAchRs). This finding suggests that combining α7-nAchRs activators (agonists, such as nicotine and PNU282987) with BACE1 inhibitors will prevent the unwanted presynaptic side-effects of blocking the BACE1 enzyme.

File Number: LS-2010-004 

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