N-truncated amyloid ß (Aß) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits.

Acta neuropathologica

PubMedID: 23685882

Bouter Y, Dietrich K, Wittnam JL, Rezaei-Ghaleh N, Pillot T, Papot-Couturier S, Lefebvre T, Sprenger F, Wirths O, Zweckstetter M, Bayer TA. N-truncated amyloid ß (Aß) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits. Acta Neuropathol. 2013;126(2):189-205.
N-truncated Aß4-42 is highly abundant in Alzheimer disease (AD) brain and was the first Aß peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Aß4-42 rapidly forms aggregates possessing a high aggregation propensity in terms of monomer consumption and oligomer formation. Short-term treatment of primary cortical neurons indicated that Aß4-42 is as toxic as pyroglutamate Aß3-42 and Aß1-42. In line with these findings, treatment of wildtype mice using intraventricular Aß injection induced significant working memory deficits with Aß4-42, pyroglutamate Aß3-42 and Aß1-42. Transgenic mice expressing Aß4-42 (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Aß4-42 correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Aß4-42 triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction.