MicroRNAs (miRNAs) are recently-discovered small regulatory RNAs that play fundamental roles in neurobiology. Preliminary results indicate that decreased expression of a particular miRNA, miR-107, may contribute to Alzheimer's disease (AD) pathogenesis through a metabolic pathway. These are the first published data pertaining to miRNAs in a specific pathway that may contribute to AD. We will test a specific strategy to target this pathway for AD therapy. Hypothesis #1: MiR-107 expression is decreased very early in AD, which increases BACE1 expression, and hence increases the amount of neurotoxic Abeta peptides in AD patients' brains. Hypothesis #2: Bezafibrate treatment decreases AD-type pathology by increasing levels of miR-107.
Specific Aim #1 : Characterize fully the regulation of BACE1 by miRNAs. Sub-Aim a. A novel technique will test directly whether BACE1 mRNA is a miRNA target. This biochemical approach involves co- immunoprecipitation using our monoclonal anti-Argonaute antibody. Sub-Aim b. Tissue culture studies will be performed to evaluate exactly which parts of the BACE1 mRNA 3'UTR constitute miRNA targets. Sub-Aim c. `Knock-in' and `knock-down' techniques will be used to alter miR-107 levels specifically in human cultured cells, to determine the effects of miR-107 expression changes on the levels of BACE1 protein, C99 polypeptide, and A2 peptide. Experiments will be performed initially on H4 and SH-SY5Y cells.
Specific Aim #2 : Characterize the impact of miR-107 on glucose metabolism and correlate the expression of miR-107 and other miRNAs with AD pathology in situ Sub-Aim a. Tissue culture studies will be performed to assess how pharmacological treatments that alter metabolism affect miR-107 expression, and to evaluate how cellular changes in miR-107 influence the levels of specific metabolic intermediaries. Sub-Aim b. Human brain in situ hybridization will be used to understand how miR-107 expression relates to pathological hallmarks of AD and non-AD dementia.
Specific Aim #3 : Evaluate bezafibrate for increasing miR-107 levels and decreasing BACE1 protein and A2 peptide(s) formation in vitro and in vivo. Bezafibrate is an orally-administered, well-tolerated medication. Sub-Aim a. Preliminary results in cultured cells demonstrated that bezafibrate causes increased miR-107 expression and also induced down-regulation of BACE1 protein. The specific mechanism of bezafibrate action will be characterized using experiments in which the levels of miR-107 are manipulated. Sub-Aim b. Bezafibrate will be administered to mice - APPNLh/NLh x PS1P264L/P264L humanized APP knock-in mutants - that are an excellent model of AD-type amyloidogenesis (1), to demonstrate in vivo the efficacy of bezafibrate in modulating miR-107, BACE1, A2 levels, and AD-type neuropathology.

Public Health Relevance

MicroRNAs are recently-discovered molecules that serve fundamental functions in the human brain. This research demonstrates for the first time that a particular microRNA may play an important role in Alzheimer's disease. A research program is proposed which exploits this new discovery, in order to develop and evaluate a novel therapy for patients at risk for Alzheimer's disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS061933-01A1
Application #
7583041
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Refolo, Lorenzo
Project Start
2008-09-30
Project End
2012-02-28
Budget Start
2008-09-30
Budget End
2009-02-28
Support Year
1
Fiscal Year
2008
Total Cost
$320,469
Indirect Cost
Name
University of Kentucky
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Brenowitz, Willa D; Han, Fang; Kukull, Walter A et al. (2018) Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer's disease pathology in older adults. Neurobiol Aging 62:64-71
Neltner, Janna H; Abner, Erin L; Jicha, Gregory A et al. (2016) Brain pathologies in extreme old age. Neurobiol Aging 37:1-11
Brenowitz, Willa D; Nelson, Peter T; Besser, Lilah M et al. (2015) Cerebral amyloid angiopathy and its co-occurrence with Alzheimer's disease and other cerebrovascular neuropathologic changes. Neurobiol Aging 36:2702-8
Brenowitz, Willa D; Monsell, Sarah E; Schmitt, Frederick A et al. (2014) Hippocampal sclerosis of aging is a key Alzheimer's disease mimic: clinical-pathologic correlations and comparisons with both alzheimer's disease and non-tauopathic frontotemporal lobar degeneration. J Alzheimers Dis 39:691-702
Hébert, Sébastien S; Wang, Wang-Xia; Zhu, Qi et al. (2013) A study of small RNAs from cerebral neocortex of pathology-verified Alzheimer's disease, dementia with lewy bodies, hippocampal sclerosis, frontotemporal lobar dementia, and non-demented human controls. J Alzheimers Dis 35:335-48
Schmitt, Frederick A; Nelson, Peter T; Abner, Erin et al. (2012) University of Kentucky Sanders-Brown healthy brain aging volunteers: donor characteristics, procedures and neuropathology. Curr Alzheimer Res 9:724-33
Jicha, Gregory A; Abner, Erin L; Schmitt, Frederick A et al. (2012) Preclinical AD Workgroup staging: pathological correlates and potential challenges. Neurobiol Aging 33:622.e1-622.e16
Rapoport, Stanley I; Nelson, Peter T (2011) Biomarkers and evolution in Alzheimer disease. Prog Neurobiol 95:510-3
Nelson, Peter T; Schmitt, Frederick A; Lin, Yushun et al. (2011) Hippocampal sclerosis in advanced age: clinical and pathological features. Brain 134:1506-18
Nelson, Peter T; Head, Elizabeth; Schmitt, Frederick A et al. (2011) Alzheimer's disease is not ""brain aging"": neuropathological, genetic, and epidemiological human studies. Acta Neuropathol 121:571-87

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