Kim_2023_Int.J.Mol.Sci_24_2092

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in pathogenesis of Azheimer's disease (AD). Sequential cleavage of APP by beta- and gamma-secretases leads to generation of Abeta40 (non-amyloidogenic) and Abeta42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) act as catalytic subunits of gamma-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 affect APP proteolysis by gamma-secretase and influence levels of generated Abeta40 and Abeta42 peptides. The predominant idea in the field is the "amyloid hypothesis" that states that the resulting increase in Abeta42:Abeta40 ratio leads to "toxic gain of function" due to the accumulation of toxic Abeta42 plaques and oligomers. An alternative hypothesis based on analysis of PS1 conditional knockout mice is that "loss of function" of gamma-secretase plays an important role in AD pathogenesis. In the present paper, we propose a mechanistic hypothesis that may potentially reconcile these divergent ideas and observations. We propose that the presence of soluble Abeta peptides in endosomal lumen (and secreted to the extracellular space) is essential for synaptic and neuronal function. Based on structural modeling of Abeta peptides, we concluded that Abeta42 peptides and Abeta40 peptides containing non-amyloidogenic FAD mutations in APP have increased the energy of association with the membranes, resulting in reduced levels of soluble Abeta in endosomal compartments. Analysis of PS1-FAD mutations also revealed that all of these mutations lead to significant reduction in both total levels of Abeta produced and in the Abeta40/Abeta42 ratio, suggesting that the concentration of soluble Abeta in the endosomal compartments is reduced as a result of these mutations. We further reasoned that similar changes in Abeta production may also occur as a result of age-related accumulation of cholesterol and lipid oxidation products in postsynaptic spines. Our analysis more easily reconciled with the "loss of gamma-secretase function" hypothesis than with the "toxic gain of Abeta42 function" idea. These results may also explain why inhibitors of beta- and gamma- secretase failed in clinical trials, as these compounds are also expected to significantly reduce soluble Abeta levels in the endosomal compartments.