Downregulation of Nrf2 deteriorates cognitive impairment in APP/PS1 mice by inhibiting mitochondrial biogenesis through the PPARγ/PGC1α signaling pathway.

Background: Mitochondrial dysfunction is considered to be an important pathogenesis of cognitive impairment in Alzheimer's disease(AD). Activation of Nrf2 can improve cognitive impairment in AD mice, but the underlying mechanism remains to be elucidated. This research aims to investigate the intrinsic molecular mechanism of Nrf2 in mitochondrial biogenesis related to cognitive impairment of AD mice.

Methods: APP/PS1 mice were used as AD model mice, and Nrf2 down-regulated mouse model was established by injecting lentivirus into hippocampus. Morris water maze test was used to evaluate the learning and memory ability of mice. The biochemical assays were used to detect the expression of Nrf2, mitochondrial biogenesis-related genes, and Aβ protein.Transmission electron microscopy was used to observe the number of mitochondria and synaptic structure in neurons. Chromatin immunoprecipitation was used to observe the binding of Nrf2 protein to the PGC1α promoter; Co-Immunoprecipitation was used to observe the interaction between PPARγ protein and PGC1α protein.

Results: Downregulation of Nrf2 reduced mitochondrial biogenesis, aggravated Aβ protein deposition and synaptic damage, and in turn aggravated cognitive impairment in mice. Compared with control mice, AD model mice had reduced levels of Nrf2, PPARγ, PGC1α, NRF1, TFAM protein, mitochondrial number and MAP2, increased Aβ protein deposition, and worsened synaptic damage and cognitive impairment. Lentivirus-induced Nrf2 downregulation downregulates PPARγ, PGC1α, NRF1, and TFAM protein expression, reduces mitochondrial number and MAP2 levels, and aggravates Aβ protein deposition, synaptic damage, and cognitive impairment. Nrf2 protein bound to the PGC1α gene promoter, and PPARγ protein interacted with PGC1α protein.

Conclusion: Nrf2 can directly regulate PGC1α transcription, and can also regulate PPARγ followed by binding to the PGC1α protein, thereby modulating mitochondrial biogenesis.Nrf2 downregulation reduces the expression of PPARγ and PGC1α proteins, thereby reducing their interaction. This suppression impairs mitochondrial biogenesis, exacerbates mitochondrial dysfunction, intensifies Aβ deposition and synaptic damage, and ultimately worsens cognitive impairment in AD mice.