An alternative interpretation of the amyloid Abeta hypothesis with regard to the pathogenesis of Alzheimer's disease

Abstract

Alzheimer's disease is a complex neurodegenerative process that is believed to be due to the accumulation of short, hydrophobic peptides derived from amyloid precursor proteins by proteolytic cleavage. It is widely believed that these Abeta peptides are secreted into the extracellular spaces of the CNS, where they assemble into toxic oligomers that kill neurons and eventually form deposits of senile plaques. This essay explores the possibility that a fraction of these Abeta peptides never leave the membrane lipid bilayer after they are generated, but instead exert their toxic effects by competing with and compromising the functions of intramembranous segments of membrane-bound proteins that serve many critical functions. Based on the presence of shared amino acid sequences containing GxxG motifs, I speculate that accumulations of intramembranous Abeta peptides might affect the functions of amyloid precursor protein itself and the assembly of the PS1, Aph1, Pen 2, Nicastrin complex.

Fig. 1.

Amino acid sequences of peptides generated by proteolytic cleavage of the APP. The yellow background highlights some of the hydrophobic amino acids that are believed to reside within the lipid bilayer of the membrane. Positively charged residues are blue, and negatively charged residues are red.

Fig. 2.

Comparison of transmembrane domains of the APP family and human erythrocyte GPA. Gray highlighted residues are considered to be the transmembrane domains, with yellow highlighting the GxxxG motifs.

Fig. 3.

Schematic diagram of the possible ways in which transmembrane APP molecules might be cleaved by different combinations of membrane-bound proteases. APP, believed to be dimeric in neuronal membranes, is depicted here as a monomer. The transmembrane orientation of APP would be reversed in intracytoplasmic membranes, with the amino terminus extending into the lumens of the ER and other cytoplasmic vesicles.

Fig. 4.

Glycophorin dimers, normally stable in SDS, are dissociated at high temperature. Under these conditions, peptide fragments generated by proteolytic cleavage of the transmembrane domain are able to associate with glycophorin monomers, creating chimeric pseudodimers. [Reproduced with permission from ref. (Copyright 1976, American Chemical Society, Washington, DC).]

Fig. 5.

A comparison of the amino acid sequences of the transmembrane segments of APP and two isoforms of Aph, a critical protein involved the assembly of the PS1/γ-secretase complex. Yellow highlighting defines the GxxxG motifs.

Fig. 6.

Both the Aβ peptides and an Aph-1 peptide have amino acid sequences that are similar to the canonical sequence LxxxGxxxGxxxT/S, thought to be a characteristic feature of transmembrane segments that are able to form stable oligomers.