PPAR[gamma]-coactivator-1[alpha] gene transfer reduces neuronal loss and amyloid-[Beta] generation by reducing [Beta]-secretase in an Alzheimer's disease model

Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying A[beta] pathology and other important hallmarks including neuronal loss. PPAR[gamma]-coactivator-1[alpha] (PGC-1[alpha]) is a cofactor for transcription factors including the peroxisome proliferator-...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS 2016-10, Vol.113 (43), p.12292
Hauptverfasser: Katsouri, Loukia, Lim, Yau M, Blondrath, Katrin, Eleftheriadou, Ioanna, Lombardero, Laura, Birch, Amy M, Mirzaei, Nazanin, Irvine, Elaine E, Mazarakis, Nicholas D, Sastre, Magdalena
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Sprache:eng
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Zusammenfassung:Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying A[beta] pathology and other important hallmarks including neuronal loss. PPAR[gamma]-coactivator-1[alpha] (PGC-1[alpha]) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1[alpha] also regulates the transcription of [beta]-APP cleaving enzyme (BACE1), the main enzyme involved in A[beta] generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1[alpha] by generating a lentiviral vector to express human PGC-1[alpha] 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-1[alpha] showed improved spatial and recognition memory concomitant with a significant reduction in A[beta] deposition, associated with a decrease in BACE1 expression. hPGC-1[alpha] 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 A[beta] pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1[alpha] gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.
ISSN:0027-8424
1091-6490