Aβ38 in the brains of patients with sporadic and familial Alzheimer's disease and transgenic mouse models.

The pathogenesis of Alzheimer's disease (AD) is believed to be closely dependent on deposits of neurotoxic amyloid-beta peptides (A beta), which become abundantly present throughout the central nervous system in advanced stages of the disease. The different A beta peptides existing are generated by subsequent cleavage of the amyloid-beta protein precursor (A beta PP) and may vary in length and differ at their C-terminus. Despite extensive studies on the most prevalent species A beta(40) and A beta(42), A beta peptides with other C-termini such as A beta(38) have not received much attention. In the present study, we used a highly specific and sensitive antibody against A beta(38) to analyze the distribution of this A beta 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 A beta(38) 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. A beta(38)-positive extracellular plaques were virtually limited to familial cases. Interestingly we observed A beta(38)-positive plaques not only among familial cases due to A beta PP mutations, but also in cases of familial AD caused by presenilin (PSEN) mutations. Furthermore we demonstrate that A beta(38) deposits in the form of extracellular plaques are common in several AD transgenic mouse models carrying either only A beta PP, or combinations of A beta PP, PSEN1, and tau transgenes.