N-Truncated A beta(2-X) Starting with Position Two in Sporadic Alzheimer's Disease Cases and Two Alzheimer Mouse Models

According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid beta-peptides (A beta s) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated A beta variants is derived from the larger amyloid-beta protein precursor (A beta PP). Vast evidence suggests that A beta(x-42) isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Ap peptides and A beta(x-42) species appear to be the crucial players in AD etiology, the A beta(2-x) isoforms did not receive much attention yet. The present study is the first to show immunohistochemical evidence of A beta(2-x) in cases of AD and its distribution in Al3PP/PS 1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using A132-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Ap deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against A13-variants starting with the N-terminal Alanine-2.