Alzheimer Research Forum Discussion: Gain or Loss of Function – Time to Shake up Assumptions on γ-Secretase in Alzheimer Disease?

Abstract

A number of mutations in presenilin (PS) 1, 2, or APP genes linked to familial AD (FAD) have been 402 Alzheimer Research Forum Discussion: Gain or Loss of Functionshown to increase the ratio of Aβ42/Aβ40 secreted from cells, or in the brains of transgenic mice overexpressing these mutant genes. As pointed out by Bentahir et al. and Kumar-Singh et al., the absolute levels of secreted Aβ40 are often significantly decreased, while those of Aβ42 are not robustly changed, resulting in an increase in the Aβ42/Aβ40 ratio.γ-secretase cleaves its substrates at multiple sites within the transmembrane domain; the γ-cleavages of APP take place at positions 40 or 42, and the γ or ε-cleavage to produce AICD at position 49. The catalytic site of γ-secretase comprising the two transmembrane aspartate residues appears to attack the scissile bonds of substrates (which are predicted to form α-helices) at a combination of multiple sites. This determines the levels of products and their relative ratios at a constant level, that is, ε-cleavage to produce AICD at position 49 and γ-cleavage to yield Aβ40 being predominant. FAD mutations cause substitutions of single amino acid residues within PS polypeptide, and these substitutions shift the preferred cleavage sites from positions 40 and 49 to 42, facilitating production of a more aggregable Aβ42 species. The precise molecular mechanism whereby FAD mutations cause the "shift" in the cleavage sites by γ-secretase remains unclear, but single amino acid substitutions in PS may subtly distort its three-dimensional structure and alter the cleavage patterns.It is currently unknown whether reduction in Aβ40 cleavage either increases the supply of substrates to the γ42-secretase within an identical protease complex or to a subcellular compartment that preferentially produces Aβ42, or whether, alternatively, all the changes take place simultaneously. In this regard, the pathological phenotype caused by FAD mutations, that is, increase in Aβ42 and decrease in Aβ40, could well be interpreted either as "gain of abnormal function" that alters the function of PS (as γ-secretase), or alternatively as "partial loss of function" when we consider the production of the major cleavage products, that is, Aβ40 or AICD, as its "normal" function.Which, then, is the pathogenic phenomenon in the brains of patients with AD, especially FAD with a PS mutation: reduction in Aβ40, reduction in AICD, or increase in Aβ42? We have to keep in mind that earlyonset FAD is an autosomal-dominant disease, in which patients harbor one mutant allele together with one wild-type (wt) allele. Indeed, heterozygous PS1 KO mice that carry one copy of wt PS1, or knock-in mice that harbor one copy each of mutant and wt PS1 (Wang R et al., J Biol Chem, in press) showed only a moderate decrease in γ-secretase activity and Aβ40 level compared to those with only one copy of mutant PS1. Moreover, FAD patients do not show any developmental abnormalities caused by decreased Notch signaling. Collectively, the levels of Aβ40 or AICD/NICD p...