Aβ 38 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-β peptides (Aβ), which become abundantly present throughout the central nervous system in advanced stages of the disease. The different Aβ peptides existing are generated by subsequent cleavage of the amyloid-β protein precursor (AβPP) and may vary in length and differ at their C-terminus. Despite extensive studies on the most prevalent species Aβ₄₀ and Aβ₄₂, Aβ peptides with other C-termini such as Aβ₃₈ have not received much attention. In the present study, we used a highly specific and sensitive antibody against Aβ₃₈ to analyze the distribution of this Aβ 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 Aβ₃₈ 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. Aβ₃₈-positive extracellular plaques were virtually limited to familial cases. Interestingly we observed Aβ₃₈-positive plaques not only among familial cases due to AβPP mutations, but also in cases of familial AD caused by presenilin (PSEN) mutations. Furthermore we demonstrate that Aβ₃₈ deposits in the form of extracellular plaques are common in several AD transgenic mouse models carrying either only AβPP, or combinations of AβPP, PSEN1, and tau transgenes.