RT Journal Article
SR Electronic
T1 Metabolic resistance of Aβ3pE-42, a target epitope of the anti-Alzheimer therapeutic antibody, donanemab
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202402650
DO 10.26508/lsa.202402650
VO 7
IS 12
A1 Iwata, Nobuhisa
A1 Tsubuki, Satoshi
A1 Sekiguchi, Misaki
A1 Watanabe-Iwata, Kaori
A1 Matsuba, Yukio
A1 Kamano, Naoko
A1 Fujioka, Ryo
A1 Takamura, Risa
A1 Watamura, Naoto
A1 Kakiya, Naomasa
A1 Mihira, Naomi
A1 Morito, Takahiro
A1 Shirotani, Keiro
A1 Mann, David MA
A1 Robinson, Andrew C
A1 Hashimoto, Shoko
A1 Sasaguri, Hiroki
A1 Saito, Takashi
A1 Higuchi, Makoto
A1 Saido, Takaomi C
YR 2024
UL http://www.life-science-alliance.org/content/7/12/e202402650.abstract
AB The amyloid β peptide (Aβ), starting with pyroglutamate (pE) at position 3 and ending at position 42 (Aβ3pE-42), predominantly accumulates in the brains of Alzheimer’s disease. Consistently, donanemab, a therapeutic antibody raised against Aβ3pE-42, has been shown to be effective in recent clinical trials. Although the primary Aβ produced physiologically is Aβ1-40/42, an explanation for how and why this physiological Aβ is converted to the pathological form remains elusive. Here, we present experimental evidence that accounts for the aging-associated Aβ3pE-42 deposition: Aβ3pE-42 was metabolically more stable than other Aβx-42 variants; deficiency of neprilysin, the major Aβ-degrading enzyme, induced a relatively selective deposition of Aβ3pE-42 in both APP transgenic and App knock-in mouse brains; Aβ3pE-42 deposition always colocalized with Pittsburgh compound B–positive 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 Aβ1-42 may be processed to Aβ3pE-42. Our findings suggest that anti-Aβ therapies are more effective if given before Aβ3pE-42 deposition.All raw data presented in the article and supplementary information are available upon request from the corresponding authors.