Grants and Contracts Details
Description
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 coimmunoprecipitation
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 Aâ 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 Aâ 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, Aâ levels, and AD-type neuropathology.
Status | Finished |
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Effective start/end date | 9/30/08 → 8/28/12 |
Funding
- National Institute of Neurological Disorders & Stroke: $1,272,262.00
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