. Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer's Disease. Cell Rep. 2018 Dec 26;25(13):3647-3660.e2. PubMed.


Please login to recommend the paper.


  1. This paper is particularly interesting due the effects the authors observed of inhibiting β-secretase in iPSC neurons carrying fAD mutations. The authors observe that fAD mutations in either APP or PSEN1 cause defective degradation of autophagosomes. Importantly, β-secretase inhibition ameliorated this defect, and complete removal of APP function could ameliorate the autophagy defects in PSEN1 fAD mutant cells. Although the authors do not discuss it, these results are strikingly reminiscent of those presented in a paper by Pera et al. in 2017, where the reduction of mitochondrial respiration and the increased apposition of the ER with mitochondria (i.e., increased mitochondria-associated endoplasmic reticulum membranes) in fibroblasts caused by loss of presenilin function could be rescued by β-secretase inhibition. The data in these papers support a critical role for the C99 fragment of APP in these phenomena (i.e., the C-terminal fragment of APP when APP has been cleaved by β-secretase but not yet by γ-secretase). As noted in a recent review/hypothesis paper (see Figure 2 in Lumsden et al., 2018), an effect common to most, if not all, of the fAD mutations in APP would appear to be increased production of the C99 fragment, with the mutations predicted to do this most effectively (i.e., those in the γ-secretase cleavage site of APP) driving the earliest fAD onset ages. The idea that the critical effect of most/all fAD mutations in APP is to increase C99 production is, I think, more parsimonious than mechanisms based on Aβ peptide length ratios or changes in Aβ peptide aggregation tendency etc. 


    . Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J. 2017 Nov 15;36(22):3356-3371. Epub 2017 Oct 10 PubMed.

    . Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer's Disease. Front Neurosci. 2018;12:533. Epub 2018 Aug 13 PubMed.

Make a Comment

To make a comment you must login or register.