A Direct Interaction Between Mitochondrial Proteins and Amyloid-&amp;#946; Peptide and its Significance for the Progression and Treatment of Alzheimer&amp;#8217;s Disease

Benek, Ondřej; Aitken, Laura; Hroch, Lukáš; Kuča, Kamil; Gunn-Moore, Frank J.; Musílek, Kamil

doi:10.2174/0929867322666150114163051

Cited by 36 publications

(22 citation statements)

References 254 publications

(364 reference statements)

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“…Severe structural and functional abnormalities of the mitochondria were observed in the immediate vicinity of A β plaques [ 7 ]. Moreover, A β gradually accumulates within the mitochondria of both living mouse models of AD and human AD brain sections, and A β has been found to directly interact with several mitochondrial proteins, for example, cyclophilin D (CypD), amyloid- β binding alcohol (ABAD) dehydrogenase, and dynamin-related protein 1 (Drp1) [ 8 ]. These interactions impair the physiological functions of mitochondria, resulting in limited electron transfer, abnormal adenosine 5′-triphosphate (ATP) production, increased production of reactive oxygen species (ROS), and altered mitochondrial morphology and mobility in AD transgenic models [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

AP39, a Mitochondria‐Targeted Hydrogen Sulfide Donor, Supports Cellular Bioenergetics and Protects against Alzheimer’s Disease by Preserving Mitochondrial Function in APP/PS1 Mice and Neurons

Zhao

Fang

Qiao

et al. 2016

Oxidative Medicine and Cellular Longevity

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Increasing evidence suggests that mitochondrial functions are altered in AD and play an important role in AD pathogenesis. It has been established that H2S homeostasis is balanced in AD. The emerging mitochondrial roles of H2S include antioxidation, antiapoptosis, and the modulation of cellular bioenergetics. Here, using primary neurons from the well-characterized APP/PS1 transgenic mouse model, we studied the effects of AP39 (a newly synthesized mitochondrially targeted H2S donor) on mitochondrial function. AP39 increased intracellular H2S levels, mainly in mitochondrial regions. AP39 exerted dose-dependent effects on mitochondrial activity in APP/PS1 neurons, including increased cellular bioenergy metabolism and cell viability at low concentrations (25–100 nM) and decreased energy production and cell viability at a high concentration (250 nM). Furthermore, AP39 (100 nM) increased ATP levels, protected mitochondrial DNA, and decreased ROS generation. AP39 regulated mitochondrial dynamics, shifting from fission toward fusion. After 6 weeks, AP39 administration to APP/PS1 mice significantly ameliorated their spatial memory deficits in the Morris water maze and NORT and reduced Aβ deposition in their brains. Additionally, AP39 inhibited brain atrophy in APP/PS1 mice. Based on these results, AP39 was proposed as a promising drug candidate for AD treatment, and its anti-AD mechanism may involve protection against mitochondrial damage.

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Section: Introductionmentioning

confidence: 99%

AP39, a Mitochondria‐Targeted Hydrogen Sulfide Donor, Supports Cellular Bioenergetics and Protects against Alzheimer’s Disease by Preserving Mitochondrial Function in APP/PS1 Mice and Neurons

Zhao

Fang

Qiao

et al. 2016

Oxidative Medicine and Cellular Longevity

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“…In addition, an age-related loss of endogenous antioxidant defense mechanisms such as superoxide dismutase (Sod), heme oxygenase 1 (Hmox1), and γ -glutamyl cysteinyl synthetase (Gclm) accelerates oxidative stress in the brain. Similarly, during the aging process, amyloid beta peptides may enter mitochondria and disrupt mitochondrial function [ 6 ]. It has also been demonstrated that proteasomal activity decreases in the aging brain; thus, the cellular ability to degrade oxidized proteins may be impaired [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Dietary Tocotrienol/γ-Cyclodextrin Complex Increases Mitochondrial Membrane Potential and ATP Concentrations in the Brains of Aged Mice

Schloesser

Esatbeyoglu

Piegholdt

et al. 2015

Oxidative Medicine and Cellular Longevity

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Brain aging is accompanied by a decrease in mitochondrial function. In vitro studies suggest that tocotrienols, including γ- and δ-tocotrienol (T3), may exhibit neuroprotective properties. However, little is known about the effect of dietary T3 on mitochondrial function in vivo. In this study, we monitored the effect of a dietary T3/γ-cyclodextrin complex (T3CD) on mitochondrial membrane potential and ATP levels in the brain of 21-month-old mice. Mice were fed either a control diet or a diet enriched with T3CD providing 100 mg T3 per kg diet for 6 months. Dietary T3CD significantly increased mitochondrial membrane potential and ATP levels compared to those of controls. The increase in MMP and ATP due to dietary T3CD was accompanied by an increase in the protein levels of the mitochondrial transcription factor A (TFAM). Furthermore, dietary T3CD slightly increased the mRNA levels of superoxide dismutase, γ-glutamyl cysteinyl synthetase, and heme oxygenase 1 in the brain. Overall, the present data suggest that T3CD increases TFAM, mitochondrial membrane potential, and ATP synthesis in the brains of aged mice.

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“…This is directly associated with mitochondrial dysfunction being an early event in AD pathogenesis, as reflected in reduced metabolism, disruption of Ca 2ϩ homeostasis, increased free radical production, and lipid peroxidation (5)(6)(7)(8)(9). A␤ also affects mitochondrial respiration (10) and activates cytochrome c release, resulting in apoptosis (11).…”

mentioning

confidence: 99%

The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy

Smilansky

Dangoor

Nakdimon

et al. 2015

Journal of Biological Chemistry

118

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The voltage-dependent anion channel 1 (VDAC1), found in the mitochondrial outer membrane, forms the main interface between mitochondrial and cellular metabolisms, mediates the passage of a variety of molecules across the mitochondrial outer membrane, and is central to mitochondria-mediated apoptosis. VDAC1 is overexpressed in post-mortem brains of Alzheimer disease (AD) patients. The development and progress of AD are associated with mitochondrial dysfunction resulting from the cytotoxic effects of accumulated amyloid ␤ (A␤). In this study we demonstrate the involvement of VDAC1 and a VDAC1 N-terminal peptide (VDAC1-N-Ter) in A␤ cell penetration and cell death induction. A␤ directly interacted with VDAC1 and VDAC1-N-Ter, as monitored by VDAC1 channel conductance, surface plasmon resonance, and microscale thermophoresis. Preincubated A␤ interacted with bilayer-reconstituted VDAC1 and increased its conductance ϳ2-fold. Incubation of cells with A␤ resulted in mitochondria-mediated apoptotic cell death. However, the presence of non-cell-penetrating VDAC1-N-Ter peptide prevented A␤ cellular entry and A␤-induced mitochondria-mediated apoptosis. Likewise, silencing VDAC1 expression by specific siRNA prevented A␤ entry into the cytosol as well as A␤-induced toxicity. Finally, the mode of A␤-mediated action involves detachment of mitochondria-bound hexokinase, induction of VDAC1 oligomerization, and cytochrome c release, a sequence of events leading to apoptosis. As such, we suggest that A␤-mediated toxicity involves mitochondrial and plasma membrane VDAC1, leading to mitochondrial dysfunction and apoptosis induction. The VDAC1-N-Ter peptide targeting A␤ cytotoxicity is thus a potential new therapeutic strategy for AD treatment. Alzheimer disease (AD)3 pathology is characterized by cognitive decline, brain synaptic dysfunction, inflammatory responses, and mitochondrial dysfunction (1). The aggregation of the amyloid ␤ peptide (A␤) is proposed to play a key role in AD pathogenesis (2). A␤ is the post-proteolytic product of sequential cleavages of amyloid precursor protein by ␤-secretase and ␥-secretase. The commonly used 42-amino acid-long A␤ (A␤42) self-aggregates into oligomers, with larger aggregates forming A␤ plaques. However, soluble A␤ oligomers were proposed to be the cytotoxic form of the protein, acting extraor/and intracellularly (3).The severity of dementia and brain hypometabolism has been previously shown to be tightly linked (4), with brain hypometabolism preceding clinical signs of AD. This is directly associated with mitochondrial dysfunction being an early event in AD pathogenesis, as reflected in reduced metabolism, disruption of Ca 2ϩ homeostasis, increased free radical production, and lipid peroxidation (5-9). A␤ also affects mitochondrial respiration (10) and activates cytochrome c release, resulting in apoptosis (11). Importantly, A␤ does not cause toxicity in cells depleted of mitochondria (12). Finally, the mitochondrial protein, the voltage-dependent anion channel (VDAC), was shown to participate...

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A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

Cited by 36 publications

References 254 publications

AP39, a Mitochondria‐Targeted Hydrogen Sulfide Donor, Supports Cellular Bioenergetics and Protects against Alzheimer’s Disease by Preserving Mitochondrial Function in APP/PS1 Mice and Neurons

AP39, a Mitochondria‐Targeted Hydrogen Sulfide Donor, Supports Cellular Bioenergetics and Protects against Alzheimer’s Disease by Preserving Mitochondrial Function in APP/PS1 Mice and Neurons

Dietary Tocotrienol/γ-Cyclodextrin Complex Increases Mitochondrial Membrane Potential and ATP Concentrations in the Brains of Aged Mice

The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy

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