Alić I, Goh PA, Murray A, Portelius E, Gkanatsiou E, Gough G, Mok KY, Koschut D, Brunmeir R, Yeap YJ, O'Brien NL, Groet J, Shao X, Havlicek S, Dunn NR, Kvartsberg H, Brinkmalm G, Hithersay R, Startin C, Hamburg S, Phillips M, Pervushin K, Turmaine M, Wallon D, Rovelet-Lecrux A, Soininen H, Volpi E, Martin JE, Foo JN, Becker DL, Rostagno A, Ghiso J, Krsnik Ž, Šimić G, Kostović I, Mitrečić D, LonDownS Consortium, Francis PT, Blennow K, Strydom A, Hardy J, Zetterberg H, Nižetić D. Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain. Mol Psychiatry. 2021 Oct;26(10):5766-5788. Epub 2020 Jul 10 PubMed. bioRxiv

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  1. This paper is a technical tour de force and elegantly demonstrates the relevance of BACE2 as an anti-amyloidogenic protease, at least in trisomy 21 cerebral organoids. It also opens the exciting possibility that SNPs in BACE2 may control the age of onset of dementia in people with Down’s syndrome. An important merit of this work is to put BACE2 back on the research agenda. For example, we still do not know when and where exactly BACE2 is expressed in the brain, which is one of the reasons why it has been difficult to understand whether BACE1 inhibitor side effects are (partly) due to BACE2 inhibition. Likewise, we still know relatively little about physiological BACE2 functions beyond APP cleavage. Such additional functions may also be affected by BACE inhibitors and therefore potentially contribute to side effects seen in the clinical trials with BACE inhibitors.

    View all comments by Stefan Lichtenthaler

  2. Human BACE2 is an aspartyl protease, encoded by the BACE2 gene on chromosome 21 (Acquati et al., 2000; Bennett et al., 2000; Lin et al., 2000). BACE2 is homologous to BACE1 (the β-secretase). These two proteins are 45 percent identical in amino acid sequence (Sun et al., 2015). BACE2 was found to cleave the Flemish mutant APP for Aβ production (Farzan et al., 2000) and it was initially considered to be another β-secretase that contributed to Alzheimer’s development in Down’s syndrome (DS) by cleaving APP for Aβ production in the amyloidogenic pathway (Saunders et al., 1999; Solans et al., 2000). However, later studies have clearly demonstrated that BACE2 is not a β-secretase. It is the θ-secretase that cleaves APP at phenylalanine 20 within the Aβ domain to produce APP CTFθ (C80) and it prevents Aβ generation (Sun et al., 2015; Sun et al., 2006). 

    Although DS patients with trisomy-21 develop typical Alzheimer’s neuropathology, including neuritic plaques and neurofibrillary tangles, approximately 30 percent will not develop dementia during their lifetimes. In this recent publication, Alić et al. reported that trisomy 21 organoids secrete more BACE2-cleaved non-amyloidogenic APP products (Aβ1-19, 1-20, and 1-34). The profile of these truncated Aβ species in CSF of the DS patients is similar to the profile from the trisomy 21 organoids. Elimination of the extra copy of the BACE2 gene resulted in AD-like pathology in pathology-negative trisomy 21 organoids, and inhibition of either β- or γ-secretase activity resulted in less plaque deposits and hyperphosphorylated tau in the trisomy-21 organoids. More interestingly, the authors showed that BACE2’s anti-amyloidogenic activity is gene-dose-dependent in DS patients, and the SNP allelic differences in BACE2 correlate with age of dementia onset in the patients.

    This is an exciting study with convincing data generated from the trisomy-21 organoids and the large cohort of patients from The London Down Syndrome Consortium (LonDownS). These results indicate that BACE2 could play a physiological role as a dose-sensitive AD suppressor in DS patients, explaining why some DS patients have delayed or no dementia. In addition to BACE2’s anti-amyloidogenic effect, recently we also discovered that BACE2 protects neuronal cells by cleavage of Kv2.1 to prevent the outward potassium currents (Liu et al., 2018), suggesting that BACE2 could be a promising therapeutic target for AD. These studies suggest that more selective and specific BACE1 inhibitors that do not affect BACE2’s protective functions are warranted for AD drug development. Regarding the effect of different BACE2 SNP alleles on Alzheimer-related pathologies and clinical manifestations, as well as the potential for using BACE2-cleaved APP products as biomarkers, a much larger sample size is needed for future study.

    References:

    Acquati F, Accarino M, Nucci C, Fumagalli P, Jovine L, Ottolenghi S, Taramelli R. The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the down critical region. FEBS Lett. 2000 Feb 18;468(1):59-64. PubMed.

    Bennett BD, Babu-Khan S, Loeloff R, Louis JC, Curran E, Citron M, Vassar R. Expression analysis of BACE2 in brain and peripheral tissues. J Biol Chem. 2000 Jul 7;275(27):20647-51. PubMed.

    Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PubMed.

    Sun X, Wang Y, Qing H, Christensen MA, Liu Y, Zhou W, Tong Y, Xiao C, Huang Y, Zhang S, Liu X, Song W. Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB J. 2005 May;19(7):739-49. PubMed.

    Farzan M, Schnitzler CE, Vasilieva N, Leung D, Choe H. BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9712-7. PubMed.

    Saunders AJ, Kim TW, Tanzi RE. BACE maps to chromosome 11 and a BACE homolog, BACE2, reside in the obligate Down’s syndrome region of chromosome 21. Science 1999 Nov 12;(286):1255a.

    Solans A, Estivill X, de La Luna S. A new aspartyl protease on 21q22.3, BACE2, is highly similar to Alzheimer's amyloid precursor protein beta-secretase. Cytogenet Cell Genet. 2000;89(3-4):177-84. PubMed.

    Sun X, He G, Song W. BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome. FASEB J. 2006 Jul;20(9):1369-76. PubMed.

    Liu F, Zhang Y, Liang Z, Sun Q, Liu H, Zhao J, Xu J, Zheng J, Yun Y, Yu X, Song W, Sun X. Cleavage of potassium channel Kv2.1 by BACE2 reduces neuronal apoptosis. Mol Psychiatry. 2018 Jul;23(7):1542-1554. Epub 2018 Apr 27 PubMed.

    View all comments by Weihong Song

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