{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n BACE2 is a protease highly homologous to BACE1 yet it has distinct substrate‐specificity and physiological functions. Rather than promoting amyloidogenic processing, BACE2 cleaves the amyloid precursor protein (APP) within the Aβ domain at a novel “theta” site, thereby precluding the formation of full‐length Aβ peptides and acting as an intrinsic suppressor of amyloidogenesis (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " Consequently, while BACE1 is the principal β‐secretase responsible for initiating Aβ generation, BACE2 redirects APP processing toward non–amyloidogenic routes, limiting the available substrate for Aβ production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond APP metabolism, BACE2 also displays important non‐neuronal functions. In pigment cells, BACE2 processes the melanocyte protein PMEL to generate functional amyloid fibrils that are critical for normal pigmentation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In pancreatic β cells, BACE2 acts as a sheddase for membrane proteins such as Tmem27, thereby influencing β‐cell mass and improving glucose homeostasis; studies in both genetic models and with inhibitors have demonstrated that diminished BACE2 activity augments insulin secretion and β‐cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In addition, BACE2 has been shown to degrade Aβ directly with high catalytic efficiency, further supporting its role as a negative regulator of amyloid pathology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Animal models that combine BACE1 and BACE2 knockout studies have revealed that BACE2 can modulate or even compensate for deficits in BACE1 activity, highlighting the non‐redundant and multifaceted roles of these enzymes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Collectively, these findings illustrate that although BACE2 is expressed in the brain, it does not contribute to amyloid plaque formation; rather, by cleaving APP within the Aβ domain it acts protectively, while also playing key roles in pigmentation and pancreatic function. \n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xiulian Sun, Guiqiong He, Weihong Song "}, {"type": "b", "children": [{"type": "t", "text": "BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.05-5632com"}], "href": "https://doi.org/10.1096/fj.05-5632com"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16816112"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16816112"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Xiulian Sun, Yingcheng Wang, Hong Qing, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FASEB J (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1096/fj.04-3426com"}], "href": "https://doi.org/10.1096/fj.04-3426com"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15857888"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15857888"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Dmitry A Ovchinnikov, Othmar Korn, Isaac Virshup, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1220748110"}], "href": "https://doi.org/10.1073/pnas.1220748110"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23754390"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23754390"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Daria Esterházy, Ina Stützer, Haiyan Wang, et al. 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