Metabolic resistance of Abeta3pE-42, epitope of the anti-Alzheimer therapeutic antibody, donanemab.

Amyloid beta peptide (Abeta) starting with pyroglutamate (pE) at position 3 and ending at position 42 (Abeta3pE-42) is a dominant species that accumulates in Alzheimer's disease (AD) brain. Consistently, a therapeutic antibody raised against this species, donanemab, has succeeded in recent clinical trials. While the primary Abeta species produced physiologically is Abeta1-40/42, an explanation for how and why this physiological Abeta is converted to the pathological form has remained elusive. The conversion of Abeta1-42 to Abeta3pE-42 is likely to take place after deposition of Abeta1-42 given that Abeta3pE-42 plaques arise significantly later than Abeta1-42 deposition in the brains of single App knock-in and APP-transgenic mice. Here, we present experimental evidence that accounts for the aging-associated Abeta3pE-42 deposition. Abeta3pE-42 is metabolically more stable than other AbetaX-42 species. Consistently, newly generated knock-in mice, AppNL-(deltaDA)-F and AppNL-(deltaDA)-Q-F, showed no detectable Abeta pathology even after aging. In addition, a deficiency of NEP facilitated Abeta3pE-42 deposition. Abeta3pE-42 is thus likely to be a probabilistic by-product of Abeta1-42 metabolism that selectively accumulates over a long-time range of brain aging. ### Competing Interest Statement The authors have declared no competing interest.