Relevance of the COPI complex for Alzheimer's disease progression in vivo.
Cellular trafficking and recycling machineries belonging to late secretory compartments have been associated with increased Alzheimer's disease (AD) risk. We have shown that coat protein complex I (COPI)-dependent trafficking, an early step in Golgi-to-endoplasmic reticulum retrograde transport, affects amyloid precursor protein subcellular localization, cell-surface expression, as well as its metabolism. We present here a set of experiments demonstrating that, by targeting subunit δ-COP function, the moderation of the COPI-dependent trafficking in vivo leads to a significant decrease in amyloid plaques in the cortex and hippocampus of neurological 17 mice crossed with the 2xTg AD mouse model. Remarkably, an improvement of the memory impairments was also observed. Importantly, human genetic association studies of different AD cohorts led to the identification of 12 SNPs and 24 mutations located in COPI genes linked to an increased AD risk. These findings further demonstrate in vivo the importance of early trafficking steps in AD pathogenesis and open new clinical perspectives.
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
Karima
K
Bettayeb
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129.
Basaraj V
BV
Hooli
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129.
Antonio R
AR
Parrado
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
Lisa
L
Randolph
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
Dante
D
Varotsis
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
Suvekshya
S
Aryal
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065;
Jodi
J
Gresack
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129.
Rudolph E
RE
Tanzi
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065; flajolm@rockefeller.edu greengard@rockefeller.edu.
Paul
P
Greengard
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065; flajolm@rockefeller.edu greengard@rockefeller.edu.
Marc
M
Flajolet
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D020755:Coat Protein Complex I / Q000378:metabolism*; D018450:Disease Progression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058225:Plaque, Amyloid / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism*
D020755:Coat Protein Complex I
Alzheimer; COPI; EWAS studies; GWAS studies; human genetic