Converging lines of evidence have highlighted the involvement of ApoE and lipoprotein receptors in the pathogenesis of sporadic Alzheimer's disease (AD). In this project, we capitalize on our recent discovery that LR11/SorLA, a novel ApoE receptor, is downregulated in AD brain, to test the hypothesis LR11 plays an early role in AD progression. This hypothesis is supported by data from us and others demonstrating that LR11: interacts with IS-amyloid precursor protein (APR), regulates APR intracellular traffic, and modulates Ad production. Based on these findings, lower levels of LR11, as occurs selectively in vulnerable neurons in AD brain, would be predicted to contribute to amyloidogenesis. The Program Project entitled """"""""Neurobiology of Mild Cognitive Impairment in the Elderly"""""""" provides an outstanding opportunity to further investigate the role of LR11 in AD pathogenesis. Our exciting preliminary studies demonstrate early changes in LR11 expression in a subset of mild cognitive impairment (MCI) cases, as well as unanticipated changes in basal forebrain neurons, and potential differences among ApoE genotypes. To extend these results as part of the program project, we will first evaluate LR11 expression across control, MCI, and AD brains, capitalizing on the wealth of collected data to assess clinicopathological and genotype correlations. Studies will also explore potential mechanisms of action of LR1T in AD brain by pursuing collaborative interactions with the other projects to evaluate links between LR11 and A(J and early neurodegenerative changes in cholinergic basal forebrain neurons. Our central hypothesis is that decreased expression and altered distribution of LR1.1 are early changes that contribute to the pathogenesis of AD. This hypothesis will be tested in the following specific aims: 1) To test the hypothesis that LR11 expression in vulnerable regions of cerebral cortex is progressively reduced in MCI and early AD vs. control brains;2) To test the hypothesis that LR11 levels are inversely linked to AB levels and amyloid burden in MCI;and 3) To test the hypothesis that LR11 is enriched in cholinergic basal forebrain neurons and that alterations in LR11 expression are correlated with progressive cholinergic dysfunction in control, MCI, and AD brains. The findings will provide new insights into the role of LR11 in AD pathogenesis, and the results may identify LR11 as a new target for AD therapeutics.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rush University Medical Center
United States
Zip Code
Kelly, Sarah C; He, Bin; Perez, Sylvia E et al. (2017) Locus coeruleus cellular and molecular pathology during the progression of Alzheimer's disease. Acta Neuropathol Commun 5:8
McKay, Erin; Counts, Scott E (2017) Multi-Infarct Dementia: A Historical Perspective. Dement Geriatr Cogn Dis Extra 7:160-171
Perez, Sylvia E; Nadeem, Muhammad; Malek-Ahmadi, Michael H et al. (2017) Frontal Cortex and Hippocampal ?-Secretase Activating Protein Levels in Prodromal Alzheimer Disease. Neurodegener Dis 17:235-241
Marquié, Marta; Normandin, Marc D; Meltzer, Avery C et al. (2017) Pathological correlations of [F-18]-AV-1451 imaging in non-alzheimer tauopathies. Ann Neurol 81:117-128
Ikonomovic, Milos D; Mi, Zhiping; Abrahamson, Eric E (2017) Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders. Ageing Res Rev 34:51-63
Krivinko, Josh M; Erickson, Susan L; Abrahamson, Eric E et al. (2017) Kalirin reduction rescues psychosis-associated behavioral deficits in APPswe/PSEN1dE9 transgenic mice. Neurobiol Aging 54:59-70
Sorrentino, Vincenzo; Romani, Mario; Mouchiroud, Laurent et al. (2017) Enhancing mitochondrial proteostasis reduces amyloid-? proteotoxicity. Nature 552:187-193
Mahady, Laura J; Perez, Sylvia E; Emerich, Dwaine F et al. (2017) Cholinergic profiles in the Goettingen miniature pig (Sus scrofa domesticus) brain. J Comp Neurol 525:553-573
Counts, Scott E; Mufson, Elliott J (2017) Regulator of Cell Cycle (RGCC) Expression During the Progression of Alzheimer's Disease. Cell Transplant 26:693-702
Powers, Brian E; Kelley, Christy M; Velazquez, Ramon et al. (2017) Maternal choline supplementation in a mouse model of Down syndrome: Effects on attention and nucleus basalis/substantia innominata neuron morphology in adult offspring. Neuroscience 340:501-514

Showing the most recent 10 out of 270 publications