Mitochondrial Dysfunction as a Predictor and Driver of Alzheimer’s Disease-Like Pathology in OXYS Rats

Abstract

Growing evidence suggests that mitochondrial dysfunction is an early event in sporadic Alzheimer's disease (AD), but the impact of mitochondrial dysfunction on the transition from healthy aging to AD remains elusive. Here we estimated the influence of mitochondrial dysfunction on the initiation of AD signs in OXYS rats, which simulate key characteristics of sporadic AD. We assessed the mitochondrial ultrastructure of pyramidal neurons of the hippocampus at the age preceding the development (age 20 days), during manifestation (4-5 months), and at the well-pronounced stages (18-24 months) of the AD-like pathology in OXYS rats. Ultrastructural alterations were collated with the amounts of proteins mediating mitochondrial dynamics [mitofusins (MFN1 and MFN2) and dynamin-1-like protein (DRP1)]; with activity of respiratory chain complexes I, IV, and V in the hippocampal mitochondria; with reactive oxygen species (ROS) production; and with expression of uncoupling protein 2 (UCP2) regulating ROS production. Already at the preclinical stage, OXYS rats showed some characteristic changes in hippocampal mitochondria, which increased in size with the manifestation and progression of AD-like pathology, including decreased activity of respiratory complexes against the background of greater fusion and formation of larger mitochondria. Signs of AD developed simultaneously with increasing dysfunction of mitochondria, with a dramatic decrease in their number, and with increased fission but without upregulation of ROS production (observed only in 20-day-old OXYS rats). Summarizing the data from our present and previous studies, we conclude that mitochondrial dysfunction appears to mediate or possibly even initiate pathological molecular cascades of AD-like pathology in OXYS rats and can be considered a predictor of the early development of the late-onset form of AD in humans.

Contribution of Mitochondrial Disfunction in the Development of Sporadic Alzheimer's Disease: Evidence From Oxys Rats

“…This rat model simulates key characteristics of AD including tau protein hyper-phosphorylation, synaptic losses, neuronal cell death, behavioral alterations, and a decrease in cognitive functions on the background of increase in APP levels, enhanced accumulation of Aβ, and formation of amyloid plaques in the brain.The genome of OXYS rats lacking the mutations in the App, Psen1, and Psen2 genes, which are specific for the early form of AD, also speaks in favor of the this model matching the particular criteria of sporadic AD . According to our data, the development and progression of AD-like pathology in OXYS rats may be caused by mitochondrial dysfunction -2016, Kolosova et al, 2017, Tyumentsev et al, 2018). Here we summarize our evidence supporting the validity of this assertion.…”

SkQ1 Suppresses the p38 MAPK Signaling Pathway Involved in Alzheimer’s Disease-Like Pathology in OXYS Rats

“…One would expect that the effects of SkQ1 as an antioxidant are mediated by the suppression of ROS production. On the other hand, we have previously shown that the development of pathological signs in rats is accompanied by increasing mitochondrial dysfunction but not an increase in ROS production [29]. The therapeutic effects of supplementation with SkQ1 on the AD-like pathology in OXYS rats are associated with improvement of the mitochondrial apparatus and better neurotrophic supply [11,15].…”

Mitochondrial dysfunction in Alzheimer's disease: Role in pathogenesis and novel therapeutic opportunities

“…These alterations comprise mitochondrial gene expression changes, age‐dependent ultrastructural differences, and decreased activity of several ETC enzymes (Complexes I, IV, and V; Stefanova et al, ). A key pathogenic finding is that mitochondrial dysfunction precedes Aβ aggregation in the OXYS rat model (Stefanova et al, ; Tyumentsev et al, ). A more direct link between mitochondrial function and aging was demonstrated in a series of experiments, whereby dampening mitochondrial ROS production prolonged lifespan in mice (Schriner et al, ).…”