| First Author | Katsouri L | Year | 2016 |
| Journal | Proc Natl Acad Sci U S A | Volume | 113 |
| Issue | 43 | Pages | 12292-12297 |
| PubMed ID | 27791018 | Mgi Jnum | J:238803 |
| Mgi Id | MGI:5824177 | Doi | 10.1073/pnas.1606171113 |
| Citation | Katsouri L, et al. (2016) PPARgamma-coactivator-1alpha gene transfer reduces neuronal loss and amyloid-beta generation by reducing beta-secretase in an Alzheimer's disease model. Proc Natl Acad Sci U S A 113(43):12292-12297 |
| abstractText | Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying Abeta pathology and other important hallmarks including neuronal loss. PPARgamma-coactivator-1alpha (PGC-1alpha) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-gamma (PPARgamma), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1alpha also regulates the transcription of beta-APP cleaving enzyme (BACE1), the main enzyme involved in Abeta generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1alpha by generating a lentiviral vector to express human PGC-1alpha and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1alpha showed improved spatial and recognition memory concomitant with a significant reduction in Abeta deposition, associated with a decrease in BACE1 expression. hPGC-1alpha overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Abeta pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1alpha gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease. |
