Generation of amyloid beta peptide with pyroglutamate at position 3 in primary cortical neurons.

The majority of amyloid beta peptide (Abeta) deposited in the brains of Alzheimer's disease (AD) patients is N-truncated, especially Abeta starting with pyroglutamate at position 3 (Abeta(3(pE))). To develop a system in which Abeta(3(pE)) is generated in primary neurons and to clarify the cyclization mechanism of N-terminal glutamate, we constructed amyloid precursor protein complementary DNAs which encoded a potential precursor for Abeta(3(pE)) by amino acid substitution and deletion. Among them, expression of NLQ construct by Sindbis virus resulted in secretion of Abeta(3(pE)) from primary neurons, whereas the N-termini of Abeta derived from NL and NLE constructs were intact. Therefore, the NLQ construct would be useful in establishing an animal model which produces Abeta(3(pE)).