Inhibiting amyloid beta (1-42) peptide-induced mitochondrial dysfunction prevents the degradation of synaptic proteins in the entorhinal cortex

Olayemi Joseph Olajide; Claudia La Rue; Andreas Bergdahl; Clifton Andrew Chapman

doi:10.3389/fnagi.2022.960314

Inhibiting amyloid beta (1-42) peptide-induced mitochondrial dysfunction prevents the degradation of synaptic proteins in the entorhinal cortex

Front Aging Neurosci. 2022 Oct 6:14:960314. doi: 10.3389/fnagi.2022.960314. eCollection 2022.

Authors

Olayemi Joseph Olajide^{1

2}, Claudia La Rue¹, Andreas Bergdahl³, Clifton Andrew Chapman¹

Affiliations

¹ Department of Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, Montreal, QC, Canada.
² Division of Neurobiology, Department of Anatomy, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.
³ Department of Health, Kinesiology and Applied Physiology, Concordia University, Montreal, QC, Canada.

Abstract

Increasing evidence suggests that mitochondrial dysfunction and aberrant release of mitochondrial reactive oxygen species (ROS) play crucial roles in early synaptic perturbations and neuropathology that drive memory deficits in Alzheimer's disease (AD). We recently showed that solubilized human amyloid beta peptide 1-42 (hAβ_1-42) causes rapid alterations at glutamatergic synapses in the entorhinal cortex (EC) through the activation of both GluN2A- and GluN2B-containing NMDA receptors. However, whether disruption of mitochondrial dynamics and increased ROS contributes to mechanisms mediating hAβ_1-42-induced synaptic perturbations in the EC is unknown. Here we assessed the impact of hAβ_1-42 on mitochondrial respiratory functions, and the expression of key mitochondrial and synaptic proteins in the EC. Measurements of mitochondrial respiratory function in wild-type EC slices exposed to 1 μM hAβ_1-42 revealed marked reductions in tissue oxygen consumption and energy production efficiency relative to control. hAβ_1-42 also markedly reduced the immunoexpression of both mitochondrial superoxide dismutase (SOD2) and mitochondrial-cytochrome c protein but had no significant impact on cytosolic-cytochrome c expression, voltage-dependent anion channel protein (a marker for mitochondrial density/integrity), and the immunoexpression of protein markers for all five mitochondrial complexes. The rapid impairments in mitochondrial functions induced by hAβ_1-42 were accompanied by reductions in the presynaptic marker synaptophysin, postsynaptic density protein (PSD95), and the vesicular acetylcholine transporter, with no significant changes in the degradative enzyme acetylcholinesterase. We then assessed whether reducing hAβ_1-42-induced increases in ROS could prevent dysregulation of entorhinal synaptic proteins, and found that synaptic impairments induced by hAβ_1-42 were prevented by the mitochondria-targeted antioxidant drug mitoquinone mesylate, and by the SOD and catalase mimetic EUK134. These findings indicate that hAβ_1-2 can rapidly disrupt mitochondrial functions and increase ROS in the entorhinal, and that this may contribute to synaptic dysfunctions that may promote early AD-related neuropathology.

Keywords: Alzheimer’s disease; acetylcholine; entorhinal cortex; mitochondria; oxidative stress; reactive oxygen species; synaptic proteins.