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. 2023 Jan 20;24(3):2092.
doi: 10.3390/ijms24032092.

Analysis of Non-Amyloidogenic Mutations in APP Supports Loss of Function Hypothesis of Alzheimer's Disease

Meewhi Kim  1 , Ilya Bezprozvanny  1   2
Affiliations

Analysis of Non-Amyloidogenic Mutations in APP Supports Loss of Function Hypothesis of Alzheimer's Disease

Meewhi Kim et al. Int J Mol Sci. .

Abstract

Proteolytic processing of amyloid precursor protein (APP) plays a critical role in pathogenesis of Azheimer's disease (AD). Sequential cleavage of APP by β- and γ-secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) act as catalytic subunits of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 affect APP proteolysis by γ-secretase and influence levels of generated Aβ40 and Aβ42 peptides. The predominant idea in the field is the "amyloid hypothesis" that states that the resulting increase in Aβ42:Aβ40 ratio leads to "toxic gain of function" due to the accumulation of toxic Aβ42 plaques and oligomers. An alternative hypothesis based on analysis of PS1 conditional knockout mice is that "loss of function" of γ-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 Aβ peptides in endosomal lumen (and secreted to the extracellular space) is essential for synaptic and neuronal function. Based on structural modeling of Aβ peptides, we concluded that Aβ42 peptides and Aβ40 peptides containing non-amyloidogenic FAD mutations in APP have increased the energy of association with the membranes, resulting in reduced levels of soluble Aβ in endosomal compartments. Analysis of PS1-FAD mutations also revealed that all of these mutations lead to significant reduction in both total levels of Aβ produced and in the Aβ40/Aβ42 ratio, suggesting that the concentration of soluble Aβ in the endosomal compartments is reduced as a result of these mutations. We further reasoned that similar changes in Aβ 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 γ-secretase function" hypothesis than with the "toxic gain of Aβ42 function" idea. These results may also explain why inhibitors of β- and γ- secretase failed in clinical trials, as these compounds are also expected to significantly reduce soluble Aβ levels in the endosomal compartments.

Keywords: APP; Alzheimer’s disease; gamma-secretase; modeling; presenilins.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Aβ peptide sequences and membrane-associated structures. (A) Full-length APP protein is shown with locations of β- and γ-secretase cleavage sites as indicated. The wild type APP amino acid sequence is shown on the insert starting from β-secretase cleavage site (671) until the end of the transmembrane domain (723). Locations of γ-secretase cleavage sites resulting in generation of Aβ40 and Aβ42 peptides (711 and 713) are indicated by arrows. The bar diagram shows domain structure of Aβ peptide that consists of transmembrane (HMEM) and extramembrane (HECM) α-helices. Locations and amino acid changes resulting from non-amyloidogenic APP-FAD mutations in HECM region are indicated below wild type sequence that is shown in green. (B) Models of Aβ peptide association with membrane in two different conformations of HECM α-helix. In model I HECM is perpendicular to the membrane, in model II HECM interacts with the membrane as a result of a 90 degree turn following HMEM. The positions of non-amyloidogenic APP-FAD mutations in HECM domain are indicated in pink. The orange-color region of HMEM is a subject to the proteolysis by γ-secretase at positions indicated by blue for Aβ40 and Aβ42.
Figure 2
Figure 2
The membrane-association energy of Aβ peptides. A membrane-association energy (EM) of Aβ peptide is plotted as a function of Aβ length resulting from γ-secretase proteolysis between positions 704 and 725. EM is calculated for M-I (blue circles) and M-II (orange circles) conformations and for M-IID conformation that corresponds to M-II conformation with Asp residue added at carboxy-terminal end of Aβ peptide (purple circles). The results were fitted (smooth lines) using Equations (1) and (2). The insert shows predicted ratio of soluble and membrane associated Aβ peptides (αβs ratio) as a function of peptide size based on Equation (4). Red dots are the αβs values calculated for Aβ40, Aβ42 and Aβ44 as indicated.
Figure 3
Figure 3
Effect of non-amyloidogenic FAD mutations in APP located in HECM domain of Aβ. The value of cd for FAD APP mutations in HECM domain of Aβ is the difference in charge resulting from mutations and calculated at isoelectric point of wild type Aβ40. D694N and E674Q are artificial mutations used for control calculations. The linear fits yield regression coefficient Rs = 0.44 (sold line, all mutants data) and 0.81 (dashed line, with D678N replaced with D694N). The insert shows predicted changes in the ratio of soluble and membrane-associated Aβ40 peptides (αβs ratio) resulting from non-amyloidogenic FAD APP mutations in in HECM domain of Aβ.
Figure 4
Figure 4
FAD-PS1 and motions of PS1 during APP proteolysis. (A,B) PS1 sequence (A) and structure (B) are color-coded for FAD-PS1 mutation groups defined in Table 1. GD is green domain, YD is yellow domain, and OD is orange domain. (C,D) The predicted motion (white arrows) of the green domain during APP cleavage—side view (C) and ECM view (D). The APP entry into active site of γ-secretase is shown by blue arrow on panel. (D–F) The predicted motion (white arrows) of orange domain during APP cleavage—ECM view (E) and cytosolic view. (F,G) The predicted motion (white arrows) of the yellow domain (CH6-YD) and APP (Blue) during APP cleavage is shown (side view). The cleavage site at VI residues of APP is shown in pink.
Figure 5
Figure 5
Model of Aβ biogenesis in the postsynaptic spines. Green membranes support active GD motion, orange membranes support active OD motion, orange areas favor accumulation of soluble Aβ40 and red membranes favor accumulation of Aβ42.
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