Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation.
Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous Abeta peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human beta-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human Abeta aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis.
Muhammad
Alim
A
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Flores
Ingrid
I
Zhang
Hong
H
Yu
Rui
R
Staniszewski
Agnieszka
A
Planel
Emmanuel
E
Herman
Mathieu
M
Ho
Lingling
L
Kreber
Robert
R
Honig
Lawrence S
LS
Ganetzky
Barry
B
Duff
Karen
K
Arancio
Ottavio
O
Small
Scott A
SA
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism; D004594:Electrophysiology; D006579:Heterozygote; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology*
D016229:Amyloid beta-Peptides