Pera M, Larrea D, Guardia-Laguarta C, Montesinos J, Velasco KR, Agrawal RR, Xu Y, Chan RB, Di Paolo G, Mehler MF, Perumal GS, Macaluso FP, Freyberg ZZ, Acin-Perez R, Enriquez JA, Schon EA, Area-Gomez E. 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.

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  1. With this paper, I think Area-Gomez, Schon, and coworkers have made a real advance in our understanding of APP’s role in Alzheimer’s disease. They show that the increased apposition of the ER and mitochondria due to lack of PSEN activity (and as seen in fibroblasts from fAD and sAD subjects) can be reversed by inhibition of β-secretase and that this has powerful consequences for energy metabolism. They see that accumulation of C99 in the ER-associated mitochondrial membranes (MAM) has significant consequences for cells’ lipid biology related to the energy metabolism effects.
     
    These observations are presented in a wider context in their recently published paper in Cell Death and Disease (Area-Gomez et al., 2018). What I find particularly appealing about their work (which is not addressed in the papers) is that the APP fAD mutation data appears largely unified by the idea of promotion of C99 formation. Also, blockage of γ-secretase cleavage of APP would be expected to be the most effective way of accumulating C99 and, consistent with this, it is mutations in APP’s γ-secretase cleavage site that can have the earliest onset ages.
     
    These papers present a parsimonious explanation for the molecular connection between fAD mutations in APP and the PSENs that does not require involvement of Aβ. In my opinion, a unifying mechanistic explanation for the fAD mutations in the PSENs is still lacking, since a simple decreased function model is incompatible with what we know of mutations in γ-secretase complex components causing familial acne inversa, but these papers are, nevertheless, a great advance.

    References:

    Area-Gomez E, de Groof A, Bonilla E, Montesinos J, Tanji K, Boldogh I, Pon L, Schon EA. A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease. Cell Death Dis. 2018 Feb 28;9(3):335. PubMed.

    View all comments by Michael Lardelli

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