Recent studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may either delay onset or slow progression of Alzheimer's disease (AD) and reduce beta amyloid (AS) deposition in transgenic mice overexpressing human amyloid precursor protein (APPrg2576). Recently published work and our preliminary studies suggest that some NSAIDs reduce the generation of A beta 1-42, the most toxic A beta, species. Although, ibuprofen lowers A Beta 1-42 / A Beta 1-40 ratio in mouse brain it is not known if it alter the process of neurodegeneration because APPrg2576 mice do not develop neurofibrillary tangles (NFT). Furthermore, the in vivo effects of A Beta deposition and NSAIDs on brain metabolism have not been studied. To address these questions we propose to use state of the art magnetic resonance spectroscopy and imaging (MRS, MRI) and positron emission tomography technology to quantitate metabolic markers in vivo and in vitro in a novel triple transgenic mouse model that harbors three mutant human genes: amyloid precursor protein (APPswe), presenilin-1 (PS1M146V) and tauP301L expressed at comparable levels. These mice accumulate A Beta, and develop NFT-like intracellular tau deposits similar to those seen in AD. We will define the metabolic effects of progressive AB deposition and NFT formation in vivo and the effects of treatment with ibuprofen on these parameters. Our preliminary studies show decreased N-acetyl aspartate and increased taurine in APPTg2576. We hypothesize that the MRS profile of aging mice will deteriorate as A Beta accumulates, potentially prior to NFT formation. A dissociation between metabolic changes detected by MRS, quantitative measures of Aft deposition and the development of NFT in vivo may indicate that non-aggregated A Beta moieties contribute to neuronal injury. Characterizing the temporal sequence of metabolic, neurochemical and neuropathological changes will allow us to better understand the neuroprotective effects of NSAIDs and help design better treatments for AD in the future.
|Choi, Ji-Kyung; Jenkins, Bruce G; Carreras, Isabel et al. (2010) Anti-inflammatory treatment in AD mice protects against neuronal pathology. Exp Neurol 223:377-84|
|McKee, Ann C; Carreras, Isabel; Hossain, Lokman et al. (2008) Ibuprofen reduces Abeta, hyperphosphorylated tau and memory deficits in Alzheimer mice. Brain Res 1207:225-36|