Isaac G. Onyango*, James P. Bennett and Gorazd B. Stokin Pages 753 - 771 ( 19 )
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 available 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 initiation 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. Mitochondrial 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 mitochondrial systems biology. We review evidence for mitochondrial impairments ranging from mitochondrial DNA (mtDNA) mutations to epigenetic modification of mtDNA, altered gene expression, impaired mitobiogenesis, oxidative stress, altered protein turnover and changed organelle dynamics (fission and fusion). We also discuss therapeutic approaches, including repurposed drugs, epigenetic modifiers, and lifestyle changes that target each level of deficiency which could potentially alter the course of this progressive, heterogeneous Disease while being cognizant that successful future therapeutics may require a combinatorial approach.
Alzheimer's disease, mitochondria, mtDNA, bioenergetics, β-amyloid, epigenetic modifiers, lifestyle changes, repurposed drugs.
Centre for Translational Medicine International Clinical Research Centre, St. Anne’s University Hospital CZ-65691, Brno, Neurodegeneration Therapeutics, 3050A Berkmar Drive Charlottesville, VA22901, Centre for Translational Medicine International Clinical Research Centre, St. Anne’s University Hospital CZ-65691, Brno