Katsouri, L;
Lim, YM;
Blondrath, K;
Eleftheriadou, I;
Lombardero, L;
Birch, AM;
Mirzaei, N;
... Sastre, M; + view all
(2016)
PPAR gamma-coactivator-1 alpha gene transfer reduces neuronal loss and amyloid-beta generation by reducing beta-secretase in an Alzheimer's disease model.
PNAS - Proceedings of the National Academy of Sciences of the United States
, 113
(43)
pp. 12292-12297.
10.1073/pnas.1606171113.
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Abstract
Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α 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-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α 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 Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.
| Type: | Article |
|---|---|
| Title: | PPAR gamma-coactivator-1 alpha gene transfer reduces neuronal loss and amyloid-beta generation by reducing beta-secretase in an Alzheimer's disease model |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.1606171113 |
| Publisher version: | http://doi.org/10.1073/pnas.1606171113 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, A beta, BACE1, growth factor, inflammation, neurodegeneration, TRANSGENIC MOUSE MODEL, NERVE GROWTH-FACTOR, PPAR-GAMMA, TRANSCRIPTIONAL COACTIVATOR, ALS MODEL, MICE, PGC-1-ALPHA, EXPRESSION, NEURODEGENERATION, MEMORY |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > The Sainsbury Wellcome Centre |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10036373 |
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