N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits

N-truncated Aβ(4-42) is highly abundant in Alzheimer disease (AD) brain and was the first Aβ peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Aβ(4-42) 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 Aβ(4-42) is as toxic as pyroglutamate Aβ(3-42) and Aβ(1-42). In line with these findings, treatment of wildtype mice using intraventricular Aβ injection induced significant working memory deficits with Aβ(4-42), pyroglutamate Aβ(3-42) and Aβ(1-42). Transgenic mice expressing Aβ(4-42) (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Aβ(4-42) correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Aβ(4-42) triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction.