title: PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer's disease model.
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.
authors: Division of Brain Sciences, Imperial College London, London W12 0NN, United Kingdom.
authors: Loukia
authors: 0000-0003-0186-6116
authors: L
authors: Katsouri
authors: Division of Brain Sciences, Imperial College London, London W12 0NN, United Kingdom.
authors: Yau M
authors: YM
authors: Lim
authors: Division of Brain Sciences, Imperial College London, London W12 0NN, United Kingdom.
authors: Katrin
authors: K
authors: Blondrath
authors: Gene Therapy, Division of Brain Sciences, Imperial College London, London W12 0NN, United Kingdom.
authors: Ioanna
authors: I
authors: Eleftheriadou
authors: Division of Brain Sciences, Imperial College London, London W12 0NN, United Kingdom.
authors: Laura
authors: L
authors: Lombardero
authors: Division of Brain Sciences, Imperial College London, London W12 0NN, United Kingdom.
authors: Amy M
authors: AM
authors: Birch
authors: Division of Brain Sciences, Imperial College London, London W12 0NN, United Kingdom.
authors: Nazanin
authors: N
authors: Mirzaei
authors: Institute for Clinical Sciences, Medical Research Council Clinical Sciences Centre, London W12 0NN, United Kingdom.
authors: Elaine E
authors: EE
authors: Irvine
authors: Gene Therapy, Division of Brain Sciences, Imperial College London, London W12 0NN, United Kingdom; m.sastre@imperial.ac.uk n.mazarakis@imperial.ac.uk.
authors: Nicholas D
authors: ND
authors: Mazarakis
authors: Division of Brain Sciences, Imperial College London, London W12 0NN, United Kingdom; m.sastre@imperial.ac.uk n.mazarakis@imperial.ac.uk.
authors: Magdalena
authors: M
authors: Sastre
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008568:Memory / Q000502:physiology; D008822:Mice, Transgenic; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000008:administration & dosage / Q000235:genetics*; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000628:therapy; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Aβ; BACE1; growth factor; inflammation; neurodegeneration