A new BACE is for therapy of Alzheimer's disease

A hallmark of Alzheimer's disease is the deposition of amyloid plaques within neural tissue. Indeed, it has been widely suggested that neural damage caused by plaque deposition is the physiological basis for the pathogenesis of Alzheimer's disease. A variety of molecular-biological studies have shown that these amyloid plaques principally comprise a 40–42 amino-acid peptide known as Aβ, which is itself a proteolytic cleavage product of a ∼770 amino-acid transmembrane protein known as Aβ precursor protein (APP). Thus, generation of Aβ from APP is considered to be a crucial requirement for the development of Alzheimer's disease.Over recent years, a significant body of work has illustrated that the processing of APP can occur via two different pathways. In the first pathway, APP is cleaved by an activity known as α-secretase to yield a soluble N-terminal sAPPα and membrane-spanning C-terminal CTFα fragments. In the second pathway, β-secretase cleaves APP into the soluble sAPPβ and membrane-spanning CTFβ fragments. Further proteolysis of CTFα by γ-secretase produces the nonpathogenic p3 fragment, whereas cleavage of CTFβ by γ-secretase generates the amyloidogenic Aβ1–40 and Aβ1–42 peptides. Thus, the initial cleavage of APP by β-secretase is the defining event in APP processing that leads to formation of amyloid plaques. The prediction that inhibition of CTFβ production should prevent Aβ amyloid plaque formation suggests that β-secretase would be an extremely attractive therapeutic target in the treatment of Alzheimer's disease.Recently, it was shown that there exist two closely related mammalian proteins, BACE1 and BACE2 (beta-site APP cleaving enzymes 1 and 2), that exhibit β-secretase activity. Both BACE1 and BACE2 are transmembrane aspartic proteases that can convert APP into sAPPβ and CTFβ. Interestingly, while BACE1 is highly expressed in mammalian brain tissue, BACE2 is not. Furthermore, inhibition of BACE1 expression in cultured cells leads to a marked decrease in the production of CTFβ and Aβ. These studies suggest that the BACE1 protein is responsible for the majority of β-secretase activity in the mammalian brain.Now, work by Luo et al. 1xMice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation. Luo, Y. et al. Nat. Neurosci. 2001; 4: 231–232CrossRef | PubMed | Scopus (674)See all References1 and Cai et al. 2xBACE1 is the major beta-secretase for generation of Aβ peptides by neurons. Cai, H. et al. Nat. Neurosci. 2001; 4: 233–234CrossRef | PubMed | Scopus (649)See all References2 has shown that BACE1 is indeed the principal β-secretase for generation of neuronal Aβ. Both groups disrupted the BACE1 gene in mice and found, perhaps unexpectedly, that homozygous BACE1−/− animals were viable and displayed no gross anatomical or physiological abnormalities. However, whereas β-secretase cleavage products can normally be detected in the supernatants of wild-type neural cell cultures, cortical cells isolated from BACE1−/− mice failed to produce detectable amounts of Aβ peptide. Moreover, it was shown that there was a profound decrease in the amount of Aβ peptides produced in the brains of BACE1−/− mutant mice (versus wild-type or heterozygous BACE1−/− mice). Taken together, these results indicate that BACE1 is indeed the major neural β-secretase.Perhaps the most intriguing consequence of this work is the implication that pharmacological inhibition of BACE1 would be an extraordinary means to prevent or treat Alzheimer's disease. The observation that BACE1−/− mice are virtually indistinguishable from wild-type mice suggests that BACE1 inhibition would be free of major side effects. To test these hypotheses, there already exists an excellent model system for studying Alzheimer's disease in mammals: transgenic mice overexpressing a mutant form of APP (APP?) develop amyloid Aβ plaques within 9–10 months of age and exhibit a variety of Alzheimer's-like neurological defects. It will be interesting to determine whether disruption of β-secretase function (by genetic deletion or pharmacological inhibition of BACE1) in APP? mice can prevent amyloidosis and onset of disease. If so, these studies will serve as the foundation for a new generation of directed therapies for Alzheimer's disease.