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A transmembrane aspartyl protease termed ß-site APP cleavage enzyme1 (BACE1) that cleaves the amyloid precursor protein (APP) which is abundant in neurons, is required for the generation of amyloid-ß (Aß) peptides implicated in the pathogenesis of Alzheimer’s Disease (AD). BACE1, enriched in neurons of the central nervous system (CNS), is a major determinant that predisposes the brain to Aß amyloidogenesis. The physiologically high levels of BACE1 activity, coupled with low levels of BACE2 and α-secretase anti-amyloidogenic activities, in neurons, is a major contributor to the accumulation of Aß in the CNS while other organs are spared. Significantly, deletion of BACE1 in APPswe; PS1E9 mice prevents both Aß deposition and age-associated cognitive abnormalities that occur in this model of Aß amyloidosis. Moreover, the Aß burden is sensitive to BACE1 dosage in young but not aged APPswe; PS1E9 …