Mechanisms of AD neurodegeneration may be independent of Aβ and its derivatives

Abstract

Alzheimer's disease (AD) is the most common cause of dementia in the aged population. Most cases are sporadic although a small percent are familial (FAD) linked to genetic mutations. AD is caused by severe neurodegeneration in the hippocampus and neocortical regions of the brain but the cause of this neuronal loss is unclear. A widely discussed theory posits that amyloid depositions of Aβ peptides or their soluble forms are the causative agents of AD. Extensive research in the last 20 years however, failed to produce convincing evidence that brain amyloid is the main cause of AD neurodegeneration. Moreover, a number of observations, including absence of correlations between amyloid deposits and cognition, detection in normal individuals of amyloid loads similar to AD, and animal models with behavioral abnormalities independent of amyloid, are inconsistent with this theory. Other theories propose soluble Aβ peptides or their oligomers as agents that promote AD. These peptides, however, are normal components of human CSF and serum and there is little evidence of disease-associated increases in soluble Aβ and oligomers. That mutants of amyloid precursor protein (APP) and presenilin (PS) promote FAD suggests these proteins play crucial roles in neuronal function and survival. Accordingly, PS regulates production of signaling peptides and cell survival pathways while APP functions in cell death and may promote endosomal abnormalities. Evidence that FAD mutations inhibit the biological functions of PS combined with absence of haploinsufficiency mutants, support a model of allelic interference where inactive FAD mutant alleles promote autosomal dominant neurodegeneration by also inhibiting the functions of wild type alleles.

Figure 1. The amyloidogenic and signaling processing of APP and other type I transmembrane proteins

The α- and ε-site cleavages of APP and other type I transmembrane (TM) proteins (blue arrows) mediated by metalloproteinases (usually ADAMs) and γ-secretase respectively, promote production of biologically active signalling peptides (termed CTFs or ICDs). The β- and γ-site cleavages of APP catalyzed by β and γ secretase (red arrows) respectively promote production of Aβ peptides. The second step of both processing pathways (γ and ε cleavages), is catalyzed by the PS/γ-secretase system. N and C, protein N- and C-terminus respectively.