Late-Onset Alzheimer's disease (LOAD) is biochemically characterized by abnormal elevations of AB peptide and increased tau phosphorylation. Recently, reduced activity ofthe Retromer complex, which is important for the recycling of transmembrane receptors from endosomes to the Trans-Golgi Network (TGN), has been implicated in the pathology of LOAD from human patient expression profiling. The importance of retromer trafficking to LOAD is supported by several studies including both mouse and Drosophila genetic models of retromer deficiency, which have increased levels of Ap peptide, neurological deficits, and in the fly, extensive neurodegeneration. Defective retromer trafficking also inhibits Wnt signaling, suggesting a pathway via glycogen synthase kinase 3 beta (GSKSp) through which retromer could alter tau phosphorylation. We hypothesize that defective retromer sorting is central to both elevated AB peptide levels and increased tau phosphorylation in LOAD and that modulating retromer trafficking levels will have a positive impact on neurodegeneration. We will test this hypothesis in transgenic Drosophila models of LOAD where human Amyloid Precursor Protein (APP) and Amyloid Precursor Protein li-secretase (BACE) or human Tau are expressed.
Our specific aims are designed to determine the molecular pathway that connects retromer deficiency to neurodegeneration and characterize novel interacting proteins that could promote retromer stability.

Public Health Relevance

of the proposed research is that given the links between defective retromer activity and Late-Onset Alzheimer's disease, it is essential to understand the molecular regulation of the retromer complex and signaling pathways it modulates in order to pharmacologically intervene and treat LOAD patients

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG008702-22
Application #
8441031
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
1997-06-15
Project End
2015-05-31
Budget Start
2011-07-01
Budget End
2012-05-31
Support Year
22
Fiscal Year
2011
Total Cost
$209,854
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Burke, Shanna L; O'Driscoll, Janice; Alcide, Amary et al. (2017) Moderating risk of Alzheimer's disease through the use of anxiolytic agents. Int J Geriatr Psychiatry 32:1312-1321
Sano, Mary; Zhu, Carolyn W; Grossman, Hillel et al. (2017) Longitudinal Cognitive Profiles in Diabetes: Results From the National Alzheimer's Coordinating Center's Uniform Data. J Am Geriatr Soc 65:2198-2204
Tripodis, Yorghos; Alosco, Michael L; Zirogiannis, Nikolaos et al. (2017) The Effect of Traumatic Brain Injury History with Loss of Consciousness on Rate of Cognitive Decline Among Older Adults with Normal Cognition and Alzheimer's Disease Dementia. J Alzheimers Dis 59:251-263
Brenowitz, Willa D; Hubbard, Rebecca A; Keene, C Dirk et al. (2017) Mixed neuropathologies and estimated rates of clinical progression in a large autopsy sample. Alzheimers Dement 13:654-662
Aguilar, Jenny I; Dunn, Matthew; Mingote, Susana et al. (2017) Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT. Neuron 95:1074-1088.e7
Jutkowitz, Eric; Kane, Robert L; Gaugler, Joseph E et al. (2017) Societal and Family Lifetime Cost of Dementia: Implications for Policy. J Am Geriatr Soc 65:2169-2175
Moheb, Negar; Mendez, Mario F; Kremen, Sarah A et al. (2017) Executive Dysfunction and Behavioral Symptoms Are Associated with Deficits in Instrumental Activities of Daily Living in Frontotemporal Dementia. Dement Geriatr Cogn Disord 43:89-99
Small, Scott A; Simoes-Spassov, Sabrina; Mayeux, Richard et al. (2017) Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer's Disease. Trends Neurosci 40:592-602
Monsell, Sarah E; Mock, Charles; Fardo, David W et al. (2017) Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology. Alzheimer Dis Assoc Disord 31:232-238
Montgomery, Valencia; Harris, Katie; Stabler, Anthony et al. (2017) Effects of Delay Duration on the WMS Logical Memory Performance of Older Adults with Probable Alzheimer's Disease, Probable Vascular Dementia, and Normal Cognition. Arch Clin Neuropsychol 32:375-380

Showing the most recent 10 out of 587 publications