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-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.