BIOLOGICAL SCIENCES: Neuroscience PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing BACE1 in an Alzheimer’s disease model Short title: PGC-1α gene therapy for Alzheimer’s disease

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 transcriptional regulator of metabolic genes, oxidative phosphorylation and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of BACE1, the main enzyme involved in amyloid-β (Aβ) generation and its expression is decreased in Alzheimer’s disease (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 post 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 pro-inflammatory 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.