Mitochondrial Complex I and β-Amyloid Peptide Interplay in Alzheimer’s Disease: A Critical Review of New and Old Little Regarded Findings

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the main cause of dementia which is characterized by a progressive cognitive decline that severely interferes with daily activities of personal life. At a pathological level, it is characterized by the accumulation of abnormal protein structures in the brain—β-amyloid (Aβ) plaques and Tau tangles—which interfere with communication between neurons and lead to their dysfunction and death. In recent years, research on AD has highlighted the critical involvement of mitochondria—the primary energy suppliers for our cells—in the onset and progression of the disease, since mitochondrial bioenergetic deficits precede the beginning of the disease and mitochondria are very sensitive to Aβ toxicity. On the other hand, if it is true that the accumulation of Aβ in the mitochondria leads to mitochondrial malfunctions, it is otherwise proven that mitochondrial dysfunction, through the generation of reactive oxygen species, causes an increase in Aβ production, by initiating a vicious cycle: there is therefore a bidirectional relationship between Aβ aggregation and mitochondrial dysfunction. Here, we focus on the latest news—but also on neglected evidence from the past—concerning the interplay between dysfunctional mitochondrial complex I, oxidative stress, and Aβ, in order to understand how their interplay is implicated in the pathogenesis of the disease.

The selective butyrylcholinesterase inhibitor UW‐MD‐95 shows symptomatic and neuroprotective effects in a pharmacological mouse model of Alzheimer's disease

“… 49 The drug may not indirectly exert its anti‐oxidant activity through specific protection of mitochondrial activity and homeostasis of the oxidative respiratory chain complex. 53 , 54 Second, UW‐MD‐95 attenuated Aβ 25‐35 ‐induced neuroinflammation. Neuroinflammation can be seen as a consequence of amyloid toxicity and its limitation by a neuroprotective drug as a symptomatic consequence of the drug treatment.…”