Mitochondrial dysfunction and oxidative damage play an important role in the pathogenesis of Alzheimer's disease (AD), and metabolic disturbances, such as reduced glucose utilization precede the ?-amyloid and tau pathology. We hypothesize that therapeutics targeting and correcting metabolic dysfunction will be efficacious in treating AD. PGC-1? enhances both mitochondrial biogenesis and expression of antioxidant enzymes, which produces neuroprotective effects both in vitro and in vivo. Sirtuins are NAD+ dependent enzymes which play important roles in regulating metabolism. SIRT3 is of particular interest since it is localized to mitochondria where it activates enzymes of energy metabolism, and protects against reactive oxygen species (ROS) by increasing MnSOD and mitochondrial glutathione concentrations, and it inhibits activation of the mitochondrial permeability transition by deacetylating cyclophilin D. We will examine whether crossing transgenic mice with increased SIRT3 expression will exert neuroprotective effects in transgenic mouse models with increased amyloid deposition (Tg19959 and APP-NL/G/F), or with increased tau phosphorylation and NFTs (P301S). We will also determine whether treatment with nicotinamide riboside (NR), which increases brain and mitochondrial NAD+ and activates SIRT1 and SIRT3, will produce neuroprotective effects in Tg19959, APP-NL/G/F or P301S transgenic mice. The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors is a group of ligand modulated transcription factors that regulate gene expression of metabolic pathways, including PGC-1?. We will determine whether the PPAR? agonist palmitoylethanolamide (PEA), the PPAR? agonist pioglitazone or the panPPAR agonist fenofibrate which modulate energy metabolism and inflammation, are neuroprotective in transgenic mouse models of AD with either APP or tau mutations. Levels of thiamine and the thiamine dependent enzymes ?-ketoglutarate dehydrogenase and transketolase are reduced in AD. Lastly, we will determine whether the lipid soluble thiamine analogue benfotiamine can reduce oxidative stress and inflammation, and is neuroprotective in transgenic mouse models of AD with either APP or tau mutations. We will utilize microPET and MRI to determine the time course of the development of impaired glucose metabolism amyloid plaques (PIB) and tau (T807), which areas show the most susceptibility, and whether these can be altered by therapeutic interventions including NR, PPAR agonists and benfotiamine. These experiments are highly significant since they may lead to novel treatments to slow or halt the cognitive impairment and neurodegenerative processes which occur in AD and related dementias.
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