β-Secretase revealed: starting gate for race to novel therapies for Alzheimer’s disease

Although remarkable progress has been made in the identification of BACE as β-secretase, there is still much to be done. For example, although BACE-mediated cleavage of APP might be important to the pathogenesis of AD, its role in normal cellular function remains unknown. This issue could be addressed by analysing transgenic mice that overexpress BACE, as well as mice that are deficient in both copies of the gene that encodes BACE. It will also be important to understand how BACE activity is regulated in the cell and how this regulation affects APP processing and Aβ production. For example, we already know that overexpression of BACE leads to decreased processing of APP by the alternative α-secretase pathway10xβ-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Vassar, R. et al. Science. 1999; 286: 735–741Crossref | PubMed | Scopus (2413)See all References10. Similarly, protein kinase C (PKC)-mediated stimulation of α-secretase results in decreased β-secretase processing of APP, which suggests that these two enzymes might compete for cleavage of APP (Ref. 23xProtein kinase C-dependent α-secretase competes with β-secretase for cleavage of amyloid-β precursor protein in the trans-Golgi network. Skovronsky, D.M. et al. J. Biol. Chem. 2000; 275: 2568–2578Crossref | PubMed | Scopus (243)See all ReferencesRef. 23). Whether dysregulation of β-secretase or α-secretase contributes to the pathogenesis of AD has yet to be tested.It is tempting to speculate that polymorphisms in the BACE gene that affect BACE function might be linked to altered risks of AD. However, the BACE gene, which has been mapped to chromosome 11 (2xA pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of β-amyloid. Mullan, M. et al. Nat. Genet. 1992; 1: 345–347Crossref | PubMed | Scopus (813)See all References, 12xMembrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Yan, R. et al. Nature. 1999; 402: 533–537Crossref | PubMed | Scopus (1098)See all References), has not yet been associated genetically with AD. Interestingly, the BACE2 gene, like the gene encoding APP, maps to the obligate Down syndrome region of chromosome 21 (12xMembrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity. Yan, R. et al. Nature. 1999; 402: 533–537Crossref | PubMed | Scopus (1098)See all References, 22xBACE maps to chromosome 11 and a BACE homolog, BACE2, reside in the obligate down syndrome region of chromosome 21. Saunders, A.J. et al. Science. 1999; 286: 1255aCrossrefSee all References), and Down syndrome patients invariably develop amyloid plaques and AD-like pathology.Finally, the discovery of BACE as β-secretase greatly facilitates the prospects for the development of potential AD therapeutics. With a target protease now in hand, it will be possible to generate small-molecule inhibitors of BACE that could reduce Aβ production. On the basis of the success of protease inhibitors to retard progression of AIDS, the future propects for protease inhibition therapy for AD appear bright. Clinical trials of such BACE inhibitors will provide valuable clues to the pathogenesis of AD. By inhibiting Aβ production and senile plaque formation, these drugs will enable us to examine the link between senile plaques and dementia, thus providing the means for testing the amyloid cascade hypothesis in vivo.