Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.

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- Michael Lardelli
  The University of Adelaide
- Posted: 13 Feb 2017
This very significant paper refutes one of the most “beautiful” sets of data supporting the amyloid hypothesis—the correlation between Aβ40:42 ratio and the mean age at onset of AD for FAD mutations in PSEN1. Figure 5 is particularly worthy of note both for its display of this lack of correlation and (my interpretation) as an example of statisticians’ sense of humor!

Notably, both this paper and the commentary on it in PNAS by Kelleher and Shen continue to focus on Aβ production and γ-secretase activity as being important for development of AD. Kelleher and Shen in particular focus on the fact that 90 percent of FAD mutations in PSEN1 lead to reduction in Aβ40 and Aβ42 production to state that, “The study by Sun et al … point[s] to loss of γ-secretase activity as the primary molecular defect imposed by pathogenic PSEN1 mutations. Thus, therapeutic strategies aimed at restoring γ-secretase activity offer a valid and complementary approach to develop disease-modifying treatments for FAD.” But do they? Their comment ignores the 10 percent of FAD mutations in PSEN1 that did not lead to reduction in Aβ40 and Aβ42 production and, despite their having originally proposed the “presenilin hypothesis” (Shen and Kelleher, 2007), they (and the Sun et al. paper) largely ignore the possibility that (as we argued in our 2016 review paper, Jayne et al., 2016) it is the presenilin proteins’ other non-γ-secretase-dependent functions that may underlie AD pathology. If decreased γ-secretase activity caused FAD and the Aβ40:42 ratio is unimportant for the disease then one would expect also to find FAD mutations in other components of the γ-secretase complex—but there are none.

In our 2016 review we suggest that changes in the non-γ-secretase functions of the presenilin holoproteins may underlie FAD. In particular, the effects of FAD mutations on lysosomal acidification are a strong candidate for the underlying defect. Sun et al.’s paper and Kelleher and Shen’s commentary have been published almost simultaneously with Fazzari et al.’s publication in Nature showing that the PLD3 gene, for which decreased expression correlates with sporadic AD risk, appears to affect lysosome function rather than APP metabolism. It would be wonderful to see the comprehensive analysis performed by Sun et al. expanded to examine the non-γ-secretase functions of PSEN1.

References:

Kelleher RJ 3rd, Shen J. Presenilin-1 mutations and Alzheimer's disease. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):629-631. Epub 2017 Jan 12 PubMed.

Shen J, Kelleher RJ. The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):403-9. PubMed.

Jayne T, Newman M, Verdile G, Sutherland G, Münch G, Musgrave I, Moussavi Nik SH, Lardelli M. Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer's Disease. J Alzheimers Dis. 2016 Apr 4;52(3):781-99. PubMed.

Fazzari P, Horre K, Arranz AM, Frigerio CS, Saito T, Saido TC, De Strooper B. PLD3 gene and processing of APP. Nature. 2017 Jan 25;541(7638):E1-E2. PubMed.

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