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

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 (hAβ1–42) 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 hAβ1–42-induced synaptic perturbations in the EC is unknown. Here we assessed the impact of hAβ1–42 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 hAβ1–42 revealed marked reductions in tissue oxygen consumption and energy production efficiency relative to control. hAβ1–42 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 hAβ1–42 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 hAβ1–42-induced increases in ROS could prevent dysregulation of entorhinal synaptic proteins, and found that synaptic impairments induced by hAβ1–42 were prevented by the mitochondria-targeted antioxidant drug mitoquinone mesylate, and by the SOD and catalase mimetic EUK134. These findings indicate that hAβ1–2 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.

Sex‐dependent cholinergic effects on amyloid pathology: A translational study

“…Aβ negatively impacts cholinergic signaling by reducing ACh synthesis and release, 16 impairing nicotinic and muscarinic receptor signaling, 42,43 inducing cholinergic neurons toxicity 44 and decreasing VAChT expression in vitro and in vivo. [45][46][47] Our data show decreased VAChT levels in App NL-G-F and App NL-F mice, supporting and expanding these reports and indicates that VAChT change is an early pathological event. These findings align with studies in AD patients, where VAChT levels inversely correlated with pathology and cognitive deficits.…”

Mapping trends and hotspots of mitochondrial dysfunction in Alzheimer’s disease from 2013 to 2022: a bibliometric analysis of global research

“…The most cited journals are the Journal of Alzheimer’s Disease and Oxidative Medicine and Cellular Longevity ( Figure 6C ). The research content in these hot journals mainly includes genetic factors for mitochondrial dysfunction ( Awasthi et al, 2021 ), mitochondrial damage caused by Aβ ( Olajide et al, 2022 ), abnormalities in calcium signaling ( Rigotto et al, 2021 ), and abnormal mitophagy ( Reddy and Oliver, 2019 ). These results of bibliometric analyses can support researchers’ access to literature and submissions in the field ( Oelrich et al, 2007 ).…”

Biomarkers for Managing Neurodegenerative Diseases

“…In AD, postmortem brain samples have significantly lower levels of mitochondrial proteins related to oxidative phosphorylation and reduced translocase of outer membrane (TOM) proteins TOM20 and TOM70 [111,112]. The deleterious relationship between impaired mitochondria and AD pathology may be bidirectional; the infiltration of Aβ into mitochondria impairs mitochondrial energy metabolism and increases oxidative stress, a driver of synaptic dysfunction and neurodegeneration [112,113]. AD patients also have compromised mitochondria in peripheral tissue, suggesting an underlying metabolic dysfunction that may contribute to early plaque formation [114].…”