2026-08-29T09:24:33Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/64922024-09-27T08:23:18Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Pera, Marta
author
Larrea, Delfina
author
Guardia-Laguarta, Cristina
author
Montesinos, Jorge
author
Velasco, Kevin R.
author
Agrawal, Rishi R
author
Xu, Yimeng
author
Chan, Robin B.
author
Di Paolo, Gilbert
author
Mehler, Mark F.
author
Perumal, Geoffrey S.
author
Macaluso, Frank P.
author
Freyberg, Zachary Z.
author
Acin-Perez, Rebeca
author
Enriquez, Jose Antonio
author
Schon, Eric A.
author
Area-Gómez, Estela
funder
Fundación Alfonso Martín Escudero
funder
Alzheimer's Drug Discovery Foundation
funder
Ellision Medical Foundation
funder
Muscular Dystrophy Association
funder
United States Department of Defense
funder
J. Willard and Alice S. Marriott Foundation
funder
National Institutes of Health (Estados Unidos)
funder
Parkinson's Disease Foundation
2018-10-19T08:00:41Z
2018-10-19T08:00:41Z
2017
EMBO J. 2017; 36(22):3356-3371
10.15252/embj.201796797
1460-2075
0261-4189
EMBO Journal
29018038
http://hdl.handle.net/20.500.12105/6492
In the amyloidogenic pathway associated with Alzheimer disease (AD), the
amyloid precursor protein (APP) is cleaved by beta-secretase to generate
a 99-aa C-terminal fragment (C99) that is then cleaved by c-secretase to
generate the beta-amyloid (Ab) found in senile plaques. In previous
reports, we and others have shown that c-secretase activity is enriched
in mitochondria-associated endoplasmic reticulum (ER) membranes (MAM)
and that ER-mitochondrial connectivity and MAM function are upregulated
in AD. We now show that C99, in addition to its localization in
endosomes, can also be found in MAM, where it is normally processed
rapidly by c-secretase. In cell models of AD, however, the concentration
of unprocessed C99 increases in MAM regions, resulting in elevated
sphingolipid turnover and an altered lipid composition of both MAM and
mitochondrial membranes. In turn, this change in mitochondrial membrane
composition interferes with the proper assembly and activity of
mitochondrial respiratory supercomplexes, thereby likely contributing to
the bioenergetic defects characteristic of AD.
eng
Alzheimer's disease
C99
MAM
Mitochondria and sphingolipids
AMYLOID PRECURSOR PROTEIN
C-TERMINAL FRAGMENT
BETA-SECRETASE ACTIVITY
ENDOPLASMIC-RETICULUM
MOUSE MODEL
OXIDATIVE STRESS
TRANSGENIC MICE
LIPID RAFTS
A-BETA
SYNAPTIC MITOCHONDRIA
Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease
journal article
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IncreasedLocalizationAPP-C99_2017.pdf
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IncreasedLocalizationAPP-C99_2017_suppl.pdf
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IncreasedLocalizationAPP-C99_2017.pdf.txt
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IncreasedLocalizationAPP-C99_2017_suppl.pdf.txt