Current Advances in Mitochondrial Targeted Interventions in Alzheimer’s Disease

Abstract

Alzheimer’s disease is the most prevalent neurodegenerative disorder and affects the lives not only of those who are diagnosed but also of their caregivers. Despite the enormous social, economic and political burden, AD remains a disease without an effective treatment and with several failed attempts to modify the disease course. The fact that AD clinical diagnosis is most often performed at a stage at which the underlying pathological events are in an advanced and conceivably irremediable state strongly hampers treatment attempts. This raises the awareness of the need to identify and characterize the early brain changes in AD, in order to identify possible novel therapeutic targets to circumvent AD’s cascade of events. One of the most auspicious targets is mitochondria, powerful organelles found in nearly all cells of the body. A vast body of literature has shown that mitochondria from AD patients and model organisms of the disease differ from their non-AD counterparts. In view of this evidence, preserving and/or restoring mitochondria’s health and function can represent the primary means to achieve advances to tackle AD. In this review, we will briefly assess and summarize the previous and latest evidence of mitochondria dysfunction in AD. A particular focus will be given to the recent updates and advances in the strategy options aimed to target faulty mitochondria in AD.

Neurotoxic β-amyloid oligomers cause mitochondrial dysfunction—the trigger for PANoptosis in neurons

“…ROS can oxidize NADH, NADPH, and glutathione bound to mitochondrial double-membrane pores and thereby promote the opening of these membrane pores. Treatment with antioxidants can help cells restore the appropriate ROS balance and reduce the damage caused by AβO to the mitochondrial double membrane; such treatment shows promising therapeutic effects in patients with MCI and in animal models of AD (Peng et al, 2020 ; Sousa et al, 2023 ).…”

Mitochondrial Targeting against Alzheimer’s Disease: Lessons from Hibernation

“…Mitochondrial deficits, as reflected in increased oxidative stress (e.g., free radical production, lipid peroxidation, oxidative protein damage) [ 29 ] and altered calcium homeostasis [ 30 ], are observed in AD patients prior to histological and clinical abnormalities [ 31 , 32 , 33 ]. By now, it is clear that the mitochondria are differentially affected in early- vs. late-stage AD and that neurons and glia may be differentially affected during disease progression, providing new opportunities for early diagnosis and intervention [ 34 ].…”

Short Overview of Oxidative Stress in Mental Disorders

“…ROS can modify the concentration gradient of Ca 2+ on either side of the cell membrane through direct damage of Ca 2+ -regulating proteins, with the mitochondrial increase of [Ca2+]. Intramitochondrial, ROS produce changes in the activity of NADH dehydrogenase, cytochrome c oxidase and ATP synthase, with direct damage to cellular energy metabolism (Sousa et al, 2023). Apart from OS, mitochondrial dysfunction can also arise due to alterations in mitochondrial DNA.…”