Mitochondrial Dysfunction in Alzheimer’s Disease and Progress in Mitochondria-Targeted Therapeutics

Flannery, Padraig J.; Trushina, Eugenia

doi:10.1007/s40473-019-00179-0

Cited by 26 publications

(29 citation statements)

References 164 publications

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“…Unexpectedly, one of the approaches shown to improve multiple health parameters in the preclinical models of AD and AD patients includes the induction of the adaptive stress response that allows to acclimate to and overcome stress stimuli [42]. The examples include a non-pharmacological strategies such as exercise [43] or caloric restriction [44,45] [46,47]. We have shown that similar cascade could be initiated by targeting mitochondrial complex I (MCI) with small molecules that mildly, but specifically inhibit MCI [48,49] All animals were kept on a 12 h-12 h light-dark cycle, with regular feeding and cage-cleaning schedule.…”

Section: Introduction 34mentioning

confidence: 99%

Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice

Stojakovic

Nesbitt

et al. 2021

JAD

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Background: Accumulation of hyperphosphorylated tau (pTau) protein is associated with synaptic dysfunction in Alzheimer’s disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown. Objective: To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on levels of human pTau, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms. Methods: CP2 was administered to male and female 3xTg-AD mice from 3.5–18 months of age. Cognitive function was assessed using the Morris water maze. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting. Results: Chronic CP2 treatment restored synaptic activity in female 3xTg-AD mice; cognitive function, levels of synaptic proteins, glucose metabolism, and energy homeostasis were improved in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), and reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β). Conclusion: CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for treating AD.

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Section: Introduction 34mentioning

confidence: 99%

Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice

Stojakovic

Nesbitt

et al. 2021

JAD

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“…They are responsible for ATP generation, reactive oxygen species (ROS) formation, intracellular calcium homeostasis, and apoptosis (Flannery and Trushina, 2019 ). Mitochondrial dynamics of fusion, fission, turnover, and transport is governed by energy demand as well as environmental stimuli (Chen and Chan, 2009 ; Flannery and Trushina, 2019 ). Mitochondria can multiply through fission and the number can reduce by the process of mitochondrial fusion.…”

Section: Mitochondria In Neurodegeneration and Alzheimer’s Diseasementioning

confidence: 99%

“…Mitochondria can multiply through fission and the number can reduce by the process of mitochondrial fusion. Defective mitochondria are removed by a well-organized process called mitophagy (Cenini and Voos, 2019 ; Flannery and Trushina, 2019 ). The brain demands high metabolic energy to function; therefore, healthy mitochondria are a prerequisite for a healthy brain.…”

Section: Mitochondria In Neurodegeneration and Alzheimer’s Diseasementioning

confidence: 99%

“…Aβ has been reported to damage mitochondria and interfere with its functioning (Lezi and Swerdlow, 2012 ). “Mitochondrial cascade hypothesis” for AD was introduced in 2004 which considers mitochondrial dysfunction as the prerequisite that further triggers the events leading to LOAD (Cenini and Voos, 2019 ; Flannery and Trushina, 2019 ). Impaired oxidative phosphorylation (OXPHOS), decreased production of ATP, and increase in oxidative stress are well documented in AD (Wang et al, 2014 ; Flannery and Trushina, 2019 ).…”

Section: Mitochondria In Neurodegeneration and Alzheimer’s Diseasementioning

confidence: 99%

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Mitochondrial Dysfunction and Alzheimer’s Disease: Role of Microglia

Agrawal

Jha

2020

Front. Aging Neurosci.

114

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In 1907, Alois Alzheimer observed, as he quoted, development of “numerous fibers” and “adipose saccules” in the brain of his diseased patient Auguste Deter. The neurodegenerative disease became known as Alzheimer’s disease (AD) and is the most common cause of dementia worldwide. AD normally develops with aging and is mostly initiated because of the imbalance between the formation and clearance of amyloid-β (Aβ). Formation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau is another hallmark of AD. Neuroinflammation plays a significant role in the development and pathology of AD. This chapter explores the role of mitochondrial dysfunction in microglia in case of AD. Mitochondrial oxidative stress in microglia has been linked to the development of AD. Elevated generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential through various mechanisms have been observed in AD. Aβ interacts with microglial receptors, such as triggering receptor expressed in myeloid cells 2 (TREM2), activating downstream pathways causing mitochondrial damage and aggravating inflammation and cytotoxicity. Fibrillar Aβ activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in microglia leading to elevated induction of mitochondrial ROS which further causes neurotoxicity. Elevated ROS in microglia causes activation of inflammatory and cell death pathways. Production of ATP, regulation of mitochondrial health, autophagy, and mitophagy in microglia play significant roles in the AD pathology. Understanding microglial physiology and mitochondrial dysfunction will enable better therapeutic interventions.

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“…More recently different lines of evidence support a role for mitochondrial dysfunction as a central event in the pathogenesis of AD, where several mitochondrial parameters such as oxygen consumption, ATP production, ROS generation, Ca 2+ signals, mitochondrial dynamic and mitophagy, are altered (Martire et al, 2015;Guo et al, 2017;Sanmartín et al, 2017;Swerdlow, 2018;Flannery and Trushina, 2019;Huang et al, 2019). Electron transfer chain enzyme activities in autopsy AD-brains show disturbances in all mitochondrial complexes, most marked in complex IV cytochrome c oxidase (COX) (Maurer et al, 2000).…”

Section: Mitochondria and Admentioning

confidence: 99%

Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor, as an Adjunctive Therapy for the Treatment of Alzheimer’s Disease

Salech

Ponce

Paula-Lima

et al. 2020

Front. Aging Neurosci.

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Mitochondrial Dysfunction in Alzheimer’s Disease and Progress in Mitochondria-Targeted Therapeutics

Cited by 26 publications

References 164 publications

Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice

Partial Inhibition of Mitochondrial Complex I Reduces Tau Pathology and Improves Energy Homeostasis and Synaptic Function in 3xTg-AD Mice

Mitochondrial Dysfunction and Alzheimer’s Disease: Role of Microglia

Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor, as an Adjunctive Therapy for the Treatment of Alzheimer’s Disease

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