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Alliance"],"accepted":{"date-parts":[[2024,9,6]]},"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:p>\n                    The amyloid \u03b2 peptide (A\u03b2), starting with pyroglutamate (pE) at position 3 and ending at position 42 (A\u03b23pE-42), predominantly accumulates in the brains of Alzheimer\u2019s disease. Consistently, donanemab, a therapeutic antibody raised against A\u03b23pE-42, has been shown to be effective in recent clinical trials. Although the primary A\u03b2 produced physiologically is A\u03b21-40\/42, an explanation for how and why this physiological A\u03b2 is converted to the pathological form remains elusive. Here, we present experimental evidence that accounts for the aging-associated A\u03b23pE-42 deposition: A\u03b23pE-42 was metabolically more stable than other A\u03b2x-42 variants; deficiency of neprilysin, the major A\u03b2-degrading enzyme, induced a relatively selective deposition of A\u03b23pE-42 in both APP transgenic and\n                    <jats:italic>App<\/jats:italic>\n                    knock-in mouse brains; A\u03b23pE-42 deposition always colocalized with Pittsburgh compound B\u2013positive cored plaques in APP transgenic mouse brains; and under aberrant conditions, such as a significant reduction in neprilysin activity, aminopeptidases, dipeptidyl peptidases, and glutaminyl-peptide cyclotransferase-like were up-regulated in the progression of aging, and a proportion of A\u03b21-42 may be processed to A\u03b23pE-42. Our findings suggest that anti-A\u03b2 therapies are more effective if given before A\u03b23pE-42 deposition.\n                  <\/jats:p>","DOI":"10.26508\/lsa.202402650","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T10:40:15Z","timestamp":1727692815000},"page":"e202402650","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Metabolic resistance of A\u03b23pE-42, a target epitope of the anti-Alzheimer therapeutic antibody, donanemab"],"prefix":"10.26508","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8721-7947","authenticated-orcid":true,"given":"Nobuhisa","family":"Iwata","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/058h74p94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Genome-Based Drug Discovery and Leading Medical Research Core Unit, Graduate School of Biomedical Sciences, Nagasaki University","place":[", 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