Are Abeta and its derivatives causative agents or innocent bystanders in AD?

Abstract

Alzheimer's disease (AD) is characterized by neurodegeneration in neocortical regions of the brain. Currently, Abeta-based theories, including amyloid depositions and soluble Abeta, form the basis of most therapeutic approaches to AD. It remains unclear, however, whether Abeta and its derivatives are the primary causative agents of neuronal loss in AD. Reported studies show no significant correlations between brain amyloid depositions and either degree of dementia or loss of neurons, and brain amyloid loads similar to AD are often found in normal individuals. Furthermore, behavioral abnormalities in animal models overexpressing amyloid precursor protein seem independent of amyloid depositions. Soluble Abeta theories propose toxic Abeta42 or its oligomers as the agents that promote cell death in AD. Abeta peptides, however, are normal components of human serum and CSF, and it is unclear under what conditions these peptides become toxic. Presently, there is little evidence of disease-associated abnormalities in soluble Abeta and no toxic oligomers specific to AD have been found. That familial AD mutations of amyloid precursor protein, PS1 and PS2 promote neurodegeneration suggests the biological functions of these proteins play critical roles in neuronal survival. Evidence shows that the PS/gamma-secretase system promotes production of peptides involved in cell surface-to-nucleus signaling and gene expression, providing support for the hypothesis that familial AD mutations may contribute to neurodegeneration by inhibiting PS-dependent signaling pathways.

Fig. 1

Amyloidogenic and signaling cleavages of APP are distinct but closely related. Both depend on the PS1/γ-secretase system. β- and γ-secretase cleavages promote production of Aβ peptides. APP and other cell surface receptors are cleaved extracellularly by metalloproteinases (MPs) and then by γ-secretase at the ε-site to promote production of biologically active CTFs (ICDs). In the nonamyloidogenic processing, APP is cleaved by α-secretase close to the extracellular face of the plasma membrane (blue arrow, see [37]). This cleavage inhibits production of Aβ peptides.