Ndufs4 knockout induces transcriptomic signatures of Alzheimer's Diseases that are partially reversed by mitochondrial complex I inhibitor

Abstract

Mitochondrial dysfunction is well documented in Alzheimers Disease (AD). However, whether it instigates the onset of AD remains unclear. We demonstrate that a reduction of complex I activity in wild type (WT) mice caused by a global knockout of Ndufs4, an accessory mitochondrial complex I subunit, was sufficient to induce transcriptomic changes in the brain reminiscent of those observed in AD patients and familial mouse models of AD. Reduced complex I activity affected expression of genes in the networks related to mitochondrial homeostasis, neuronal and synaptic function. Transcriptomic signatures in male and female Ndufs4-/-mice reflected a different severity of AD phenotype. Unexpectedly, these changes were partially rescued by a neuroprotective small molecule mild complex I inhibitor CP2. Consistent with studies in AD mice, CP2 treatment in Ndufs4-/- mice augmented the expression of genes associated with mitochondrial biogenesis and turnover, synaptic activity, autophagy, redox balance, and reduced expression of genes related to inflammation. Female Ndufs4-/- mice demonstrated a greater reversal of gene expression toward WT mice. These studies provide further support for mitochondria as a causative factor of AD pathophysiology and complex I as a putative therapeutic target.