Beta-Secretase, APP and Aβ in Alzheimer's disease

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Alzheimer's disease (AD) is characterized by brain lesions called amyloid plaques, extracellular deposits of the beta-amyloid peptide (Aβ). Familial forms of AD are caused by genetic mutations that increase production of the long, fibrillogenic Aβ42 form of the peptide, suggesting Aβ42 plays an early central role in AD pathogenesis. Aβ is generated from the amyloid precursor protein (APP) by two proteases called β- and γ-secretase. The β-secretase, a novel transmembrane aspartic protease we originally termed β-site APP cleaving enzyme (BACE), was discovered simultaneously by several groups in 1999. BACE is required for the generation of all forms of Aβ, including Aβ42, and therefore is a prime therapeutic target for the treatment of AD. BACE knockout mice are devoid of Aβ production and amyloid plaque formation, evidence that BACE is the authentic β-secretase, and thus it represents a promising drug target.

As we will hear at this symposium, recent promising advances have been made toward the identification of BACE inhibitor drugs. However, the development of BACE drugs has also proven challenging. Other targets upstream of BACE responsible for the regulation of enzyme levels and activity should be identified and evaluated, as they may offer alternative or complementary therapeutic strategies as opposed to direct BACE inhibition. Of particular relevance in this regard is the observation that BACE levels are elevated in AD brain, suggesting increased BACE levels may play a role in AD pathogenesis. If so, normalizing BACE levels may prove therapeutically efficacious while still allowing normal BACE function. Interestingly, impaired glucose metabolism occurs early in AD, and our work has demonstrated that glucose deprivation increases BACE levels and Aβ production in the brains of an APP transgenic model of AD, the Tg2576 mouse. We have identified the molecular mechanism of the BACE increase and showed that glucose deprivation induces phosphorylation of the translation initiation factor eIF2α(eIF2α-P), which in turn increases the translation of BACE. Pharmacologically inducing eIF2α phosphorylation directly increases BACE levels. Conversely, genetically preventing eIF2α phosphorylation blocks the glucose deprivation-induced BACE increase. Chronic glucose deprivation in Tg2576 mice increases levels of eIF2α-P, BACE, Aβ, and amyloid plaques. Importantly, eIF2α-P and BACE are elevated in aggressive plaque-forming 5XFAD transgenic mice, and BACE, eIF2α-P, and amyloid load are all correlated in humans with AD. Amyloid itself also appears to increase eIF2α-P and BACE in vivo. These results strongly suggest that eIF2α phosphorylation increases BACE levels and causes Aβ overproduction, which could be an early, initiating molecular mechanism in sporadic AD. Taken together, our work is consistent with the hypothesis that impaired glucose metabolism may lead to increased BACE levels by the eIF2α-P translational mechanism, and subsequent elevation of Aβ generation. Once amyloid plaques form, Aβ causes BACE levels to increase further, thus accelerating Aβ generation and plaque growth via a positive-feedback loop. (Robert Vassar, Northwestern University) ...http://www.nyas.org/events/eventDetail.asp?eventID=13408&date=3/24/2009

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