Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice

Abstract

Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership–AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.

γ-Glutamyl-Transpeptidase-Resistant Glutathione Analog Attenuates Progression of Alzheimer’s Disease-like Pathology and Neurodegeneration in a Mouse Model

“…We followed a protocol described previously [ 20 , 21 ]. Briefly, for histopathological analyses, mice were sacrificed and perfused intracardially with 4% paraformaldehyde and cryoprotected in 30% sucrose solution.…”

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

“…[ 64 APPswe mice [79] APP/PS1 mice [73,82,88,250,[268][269][270] Tg4-42 mice [78,271] 5×FAD mice [81,85,256,272,273] 3×Tg rats [274] APP23 mice [275] McGill-R-Thy1-APP rats…”

Generation of Reactive Oxygen Species by Mitochondria

“…It is possible that mitochondrial ROS-driven glycolytic switch reprograms neuron metabolism in such a way that the production of energy through glycolysis does not match the high energetic demands of the neuron, thus, facilitating its entry into apoptosis. Interestingly, modulation of CI has been associated with development of both PD and Alzheimer's disease (AD; [116][117][118]). Given that CI can undergo activation and deactivation, and both are related to different modes of ROS production, it would be important to ascertain whether the different physiological states of CI are related to the pathogenesis in neurological disorders.…”