The advent of new imaging technologies has allowed the analysis of brain energy metabolism. A number of studies have now documented that glucose utilization is impaired in brain regions involved in memory and cognition in AD patients. Significantly, familial AD patients exhibited impaired cerebral glucose metabolism in advance of symptomatic onset and in the absence of detectable structural changes in the brain . It is now possible to employ positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to evaluate glucose metabolism as an early biomarker for AD. Additionally, several independent studies have shown a link between the Apoe4 allele and glucose utilization in the brain. These studies detect an Apoe4 dose-dependent impairment in glucose utilization in brain regions affected by the disease [93-97]. Bookheimer and colleagues have found, using fMRI, that memory recall tasks stimulated glucose utilization in regions affected by Alzheimer's disease and this effect was more pronounced in ApoeE4 carriers in comparison to those who expressed the Apoe3 allele .
PPARy plays critical roles in energy metabolism due to its direct effects on mitochondrial function and ultimately ATP production. Mitochondria may be key players in cerebral hypometabolism observed in AD, as this organelle plays critical roles in both energy metabolism as well as neuronal apoptosis. In the diseased brain, the numbers of neuronal mitochondria are greatly reduced and those remaining have very distinct morphological changes in their size and the number or cristae they contain. These morphological changes are seen mainly in neurons that have lost their dendritic arborization . Therefore, therapeutic strategies that aim at maintaining mitochondrial integrity are of importance.
PPARy activation by its agonist pioglitazone resulted in a significant increase in mitochondrial DNA copy number as well as the expression of genes that are involved in mitochondrial biogenesis in fat tissue . A recent study has found analogous changes within the brain in response to oral rosiglitazone treatment . Indeed, PPARy activation stimulated brain mitochondrial biogenesis and this stimulation was dependent on the ApoE isoform . PPARy may elicit these changes through the peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) family of proteins, these coactivators positively regulate mitochondrial function and oxidative metabolism . PPARy has been reported to stimulate the expression of PGC-1 a , which in turn, induces expression of the uncoupling proteins which stimulate mitochondrial biogenesis and respiration in muscle cells [103-105]. PGC-1 also stimulates the expression of a variety of genes that are vital for the oxidative phosphorylation pathway as well as duplication of mitochondrial DNA content [106,107].
Significantly, PGC-1a knockout mice also show lesions in the brain regions affected in Alzheimer's disease . It should be noted that TZD agonists of PPARy have a number of effects on mitochondrial metabolism, many of which are receptor-independent actions of the drugs . Roses et al. have postulated that the PPAR agonists act to improve mitochondrial function and this may be the basis of their beneficial effects on memory and cognition in AD patients .
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