Mitochondrially-Targeted Therapeutic Strategies for Alzheimer’s Disease

Abstract

: Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disease and the most common cause of dementia among older adults. There are no effective treatments avail- able for the disease, and it is associated with great societal concern because of the substantial costs of providing care to its sufferers, whose numbers will increase as populations age. While multiple causes have been proposed to be significant contributors to the onset of sporadic AD, increased age is a unifying risk factor. In addition to amyloid-β (Aβ) and tau protein playing a key role in the initi- ation and progression of AD, impaired mitochondrial bioenergetics and dynamics are likely major etiological factors in AD pathogenesis and have many potential origins, including Aβ and tau. Mito- chondrial dysfunction is evident in the central nervous system (CNS) and systemically early in the disease process. Addressing these multiple mitochondrial deficiencies is a major challenge of mito- chondrial systems biology. We review evidence for mitochondrial impairments ranging from mito- chondrial DNA (mtDNA) mutations to epigenetic modification of mtDNA, altered gene expres- sion, impaired mitobiogenesis, oxidative stress, altered protein turnover and changed organelle dy- namics (fission and fusion). We also discuss therapeutic approaches, including repurposed drugs, epigenetic modifiers, and lifestyle changes that target each level of deficiency which could poten- tially alter the course of this progressive, heterogeneous Disease while being cognizant that success- ful future therapeutics may require a combinatorial approach.

Alzheimer’s Disease and Inflammaging

“…Microglial cells activated via the M1 pathway are found around amyloid plaques and neurons containing neurofibrils in AD [ 181 ]. Microglia recognizes Aβ through a number of receptor complexes, including CD14, TLR2, TLR4, α6β1 integrin, CD47, and CD36, and are capable of phagocytizing amyloid [ 182 ]. On the one hand, the accumulation of Aβ in the brain of AD patients may be associated with impaired phagocytosis of amyloid by microglia [ 183 ].…”

Therapeutic Potential of Targeting Mitochondria for Alzheimer’s Disease Treatment

“…The maintenance of a functional mitochondrial population during the life of neurons is of paramount importance and involves a fine regulation of mitochondrial dynamics, maintained by the coordinated interplay between mechanisms of mitochondrial fusion and fission [77,78], biogenesis [79] and mitophagy [80] (Figure 1). Thus, it is easy to imagine how the interruption of any of these mitochondrial processes has a strong impact on cellular viability and functions, since neurons in particular, on the one hand, require an incredibly high amount of energy for neurotransmission, and on the other, they need an efficient system to eliminate damaged mitochondria (for refs, see [63]) and reduce ROS-induced death [63,81].…”

“…The Aβ peptides themselves interact with an NH 2 -derived neurotoxic Tau fragment of the human Tau40 isoform (441 amino acids) in human AD synapses in association with mitochondrial ANT, a condition that further worsens mitochondrial dysfunction by aggravating the impairment of the ANT, thus leading to a strong energy metabolism deficit [46,54,55]. Aβ peptides have also been shown to interact with mitochondrial matrix components altering mitochondrial dynamics by differentially modulating fission/fusion proteins (for refs, see [63]). Finally, the effects of Aβ aggregation can be mitigated by efficient mitochondrial proteostasis (for refs, see [63]).…”

“…Aβ peptides have also been shown to interact with mitochondrial matrix components altering mitochondrial dynamics by differentially modulating fission/fusion proteins (for refs, see [63]). Finally, the effects of Aβ aggregation can be mitigated by efficient mitochondrial proteostasis (for refs, see [63]).…”

Protective mechanism of gold nanoparticles on human neural stem cells injured by β-amyloid protein

“…The present results showed that miR-21-5p was unregulated in AuNPs treated cells, while the effect of AuNPs treatment on hNSCs was reversed after transfection with miR-21-5p inhibitor. Differential miRNA expression may be the result of AuNPs playing a role in cells and in promoting cells against Aβ.In addition to Aβ and tau protein being involved in the initiation and progression of AD, impaired mitochondrial bioenergetics and dynamics are likely major etiological factors in AD pathogenesis(Onyango et al 2021). Several reports had demonstrated the neuroprotection effects of AuNPs in different aspects.…”