Senile plaques that contain beta amyloid (Ass) and neurofibrillary tangles (NFT) with phosphorylated tau are the pathological hallmarks of Alzheimer's disease (AD). Ass peptides, especially Ass42, are thought to play a key role in the pathogenesis of AD. We found that ibuprofen, a non-steroidal anti-inflammatory drug (NSAID) with Ass42- lowering effects, reduces Ass deposition, NFT and cognitive decline in a novel triple transgenic mouse model of AD (3xTg-AD) that develops both senile plaques and NFT. R-flurbiprofen, an enantiomer of the NSAID flurbiprofen that lowers Ass42 but lacks cyclooxygenase inhibition reduces Ass burden in AD transgenic mice and is currently being tested in a phase III AD clinical trial. We found that oral R-flurbiprofen is well tolerated and detectable in transgenic mouse brain. Scyllo-inositol, an isomer of cyclohexanahexol, inhibits Ass oligomers formation and, when orally administered to AD transgenicyc mice, reduces Ass aggregation and deposition, and reduces cognitive decline. Importantly, scyllo-inositol is nontoxic, normally present in brain, and can be detected by magnetic resonance spectroscopy (MRS). A major goal of our proposal is to use the 3xTg-AD model and a double transgenic PSAPP model, that does not develop NFT but develops more widespread and rapid Ass deposition, to assess the prophylactic and therapeutic effects of scyllo-inositol and a second isomer of cyclohexanahexol, myo-inositol, alone and in combination with R-flurbiprofen. We hypothesize that cyclohexanehexols will reduce the neurotoxicity of Ass and improve the neurochemical profile and cognitive performance of transgenic mice by decreasing the oligomerization of Ass42 and that combination therapy with R-flurbiprofen, which reduces Ass deposition through an entirely different mechanism of action, will have an additive therapeutic effect. Our preliminary studies show that we can detect a 3-4 fold increase in scyllo-inositol levels in the brains of transgenic mice treated with scyllo-inositol using MRS and that the treatment improves long-term memory in both transgenic mouse models. Preliminary studies using myo-inositol show that it is well tolerated in mice.
The aims of the present proposal are: 1) To assess, the metabolic, histopathological, biochemical and cognitive profiles of double and triple transgenic mice treated with oral scyllo- or myo-inositol either before or after pathology has been established. Chiro-inositol, which has no effects on Ass, will be used as a control. Behavioral effects will be studied using radial arm water maze and biochemical and histological effects will be studied using western blot, ELISA, MRS and quantitative immunocytochemistry;2) To assess whether combination therapy with R-flurbiprofen and the most effective cyclohexanahexol compound defined in aim 1 will have additive therapeutic effects using the parameters defined in aim 1. We will also perform serial MRS on mice at defined ages to assess the longitudinal effects of combination therapy on metabolic profiles. Our proposed research will investigate diagnostic methods and potential therapeutics integrating state of the art imaging, neuropathological and biochemical techniques to help design strategies to prevent and treat AD.

Public Health Relevance

Relevance Alzheimer's disease is a relentlessly progressive, invariably fatal, disorder affecting millions of older Americans and costing the U.S. government billions of dollars in health care annually. In this proposal we will use a genetically modified mouse model that expresses human Alzheimer genes to study how we can treat the pathologies that are due to the accumulation of abnormal proteins in the brain. We will use therapeutic agents in living mice and monitor the disease progression with state-of-the-art imaging techniques and correlate findings with immunohistochemical findings. These studies will lay important groundwork for the future development of better approaches to detect and treat Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG031896-05
Application #
8522099
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Refolo, Lorenzo
Project Start
2009-09-15
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$360,859
Indirect Cost
$51,030
Name
Boston University
Department
Neurology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Choi, Ji-Kyung; Carreras, Isabel; Aytan, Nur et al. (2014) The effects of aging, housing and ibuprofen treatment on brain neurochemistry in a triple transgene Alzheimer's disease mouse model using magnetic resonance spectroscopy and imaging. Brain Res 1590:85-96
Korkmaz, Orhan Tansel; Aytan, Nurgul; Carreras, Isabel et al. (2014) 7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis. Neurosci Lett 566:286-91
Aytan, Nurgul; Choi, Ji-Kyung; Carreras, Isabel et al. (2013) Combination therapy in a transgenic model of Alzheimer's disease. Exp Neurol 250:228-38
Carreras, Isabel; McKee, Ann C; Choi, Ji-Kyung et al. (2013) R-flurbiprofen improves tau, but not Aß pathology in a triple transgenic model of Alzheimer's disease. Brain Res 1541:115-27
Choi, Ji-Kyung; Carreras, Isabel; Dedeoglu, Alpaslan et al. (2010) Detection of increased scyllo-inositol in brain with magnetic resonance spectroscopy after dietary supplementation in Alzheimer's disease mouse models. Neuropharmacology 59:353-7
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