Aß38 in the brains of patients with sporadic and familial Alzheimer's disease and transgenic mouse models.

ABSTRACT

The pathogenesis of Alzheimer's disease (AD) is believed to be closely dependent on deposits of neurotoxic amyloid-ß peptides (Aß), which become abundantly present throughout the central nervous system in advanced stages of the disease. The different Aß peptides existing are generated by subsequent cleavage of the amyloid-ß protein precursor (AßPP) and may vary in length and differ at their C-terminus. Despite extensive studies on the most prevalent species Aß40 and Aß42, Aß peptides with other C-termini such as Aß38 have not received much attention. In the present study, we used a highly specific and sensitive antibody against Aß38 to analyze the distribution of this Aß species in cases of sporadic and familial AD, as well as in the brains of a series of established transgenic AD mouse models. We found Aß38 to be present as vascular deposits in the brains of the majority of sporadic AD cases, whereas it is largely absent in non-demented control cases. Aß38-positive extracellular plaques were virtually limited to familial cases. Interestingly we observed Aß38-positive plaques not only among familial cases due to AßPP mutations, but also in cases of familial AD caused by presenilin (PSEN) mutations. Furthermore we demonstrate that Aß38 deposits in the form of extracellular plaques are common in several AD transgenic mouse models carrying either only AßPP, or combinations of AßPP, PSEN1, and tau transgenes.