Overview

The protein amyloid is invariably deposited in the brains of patients with all forms of Alzheimer's disease (AD). It is composed of a secreted peptide (Aβ) that can be either 40 or 42 amino acids long (Aβ 1-40 or Aβ 1-42). Aβ 1-42 forms insoluble amyloid fibrils and is deposited early and selectively in the senile plaques that are a pathological hallmark of AD. Our recent studies of plasma Aβ indicate that genetic elevation of Aβ plays a major role in typical late onset AD. This has important therapeutic implications, which we are pursuing using a transgenic mouse model for AD. In addition, we are investigating the possibility that plasma Aβ may be an excellent biomarker of AD and are searching for the genetic determinants that increase Aβ in typical late onset AD.

The amyloid that is invariably deposited in the brains of patients with all forms of Alzheimer's disease (AD) is composed of a peptide β amyloid, (Aβ) that is derived from a set of larger proteins collectively referred to as the amyloid protein precursor (APP). Studies in my laboratory and others have established that normal processing of the APP releases secreted Aβ essentially identical to the Aβ that forms insoluble amyloid fibrils in AD brain.

Most secreted Aβ is Aβ1-40 but ~10% is Aβ1-42. Aβ1-42 forms insoluble amyloid fibrils more rapidly that Aβ1-40 in vitro, and Aβ1-42 is deposited early and selectively in the senile plaques that are a pathological hallmark of AD. It is now well established that early onset, autosomal dominant familial AD (FAD) can be caused by mutations in the APP, presenilin 1 (PS1), and presenilin 2 (PS2) genes.

Using sensitive assays that distinguish Aβ1-40 from Aβ1-42, we have shown that each of the many FAD-linked APP, PS1, and PS2 mutations that we have examined increases the extracellular concentration of Aβ1-42 in vivo. This provides strong evidence that these mutations all cause AD by increasing the concentration of the highly amyloidogenic Aβ1-42 peptide thereby fostering Aβ aggregation.

Our recent studies of plasma Aβ indicate that genetic elevation of Aβ also plays a major role in typical late onset AD. This has important therapeutic implications that we are pursuing using a transgenic mouse model of AD that shows appropriate histopathological and behavioral changes. In addition, we are investigating the possibility that plasma Aβ may be an excellent premorbid biomarker of AD, and we are searching for the genetic determinants that increase Aβ in typical late onset AD.