Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

Pyroglutamate-modified Aβ peptides at amino acid position three (AβpE3–42) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). AβpE3–42 is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work was to study the direct effect of elevated AβpE3–42 levels on ongoing AD pathology using transgenic mouse models. To this end, we generated a novel mouse model (TBA42) that produces AβpE3–42. TBA42 mice showed age-dependent behavioral deficits and AβpE3–42 accumulation. The Aβ profile of an established AD mouse model, 5XFAD, was characterized using immunoprecipitation followed by mass spectrometry. Brains from 5XFAD mice demonstrated a heterogeneous mixture of full-length, N-terminal truncated, and modified Aβ peptides: Aβ1–42, Aβ1–40, AβpE3–40, AβpE3–42, Aβ3–42, Aβ4–42, and Aβ5–42. 5XFAD and TBA42 mice were then crossed to generate transgenic FAD42 mice. At 6 months of age, FAD42 mice showed an aggravated behavioral phenotype compared with single transgenic 5XFAD or TBA42 mice. ELISA and plaque load measurements revealed that AβpE3 levels were elevated in FAD42 mice. No change in Aβx–42 or other Aβ isoforms was discovered by ELISA and mass spectrometry. These observations argue for a seeding effect of AβpE-42 in FAD42 mice.