Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease

Reddy, P. Hemachandra; Beal, M. Flint

doi:10.1016/j.molmed.2007.12.002

Cited by 817 publications

(682 citation statements)

References 95 publications

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“…The Aβ peptide can also potentially cause mPTP opening in vivo as it induces mitochondrial swelling, decreases mitochondrial membrane potential, and potentiates the effect of mPTP inducers in isolated brain mitochondria (Du et al., 2008; Moreira, Santos, Moreno, & Oliveira, 2001; Shevtzova, Kireeva, & Bachurin, 2001). This can be due to an indirect effect on the pore as the Aβ peptide has the ability to enhance intracellular calcium (Abramov, Canevari, & Duchen, 2004; Chin, Tse, Harris, & Jhamandas, 2006) and to induce oxidative stress (Lustbader et al., 2004; Reddy & Beal, 2008), which is increasingly recognized as a key factor in neurodegenerative disorders. These effects are possible mechanisms contributing to mPTP opening.…”

Section: Evidence For the Involvement Of Mptp Opening In Age‐associatmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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SummaryThe cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.

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Section: Evidence For the Involvement Of Mptp Opening In Age‐associatmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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“…2) [24,83,98,101,102]. Decreases in enzymatic antioxidant defense capacity, including multiple superoxide dismutases (SOD), peroxiredoxins, and glutathione [103,104], further exacerbates oxidative damage [83,85,98,100]. Oxidative damage of multiple cellular components has been documented in both preclinical models of AD and in persons with the disease [102,105].…”

Section: Oxidative Damage As a Therapeutic Targetmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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“…The accumulation of mtDNA changes might increase ROS production and [128] reduce mitochondrial ATP in an age-dependent manner. Increases in somatic mtDNA in aging might contribute to AD development (for a review, [121]). In brain aging, mitochondrial biogenesis might represent a compensatory response to longitudinal declines in brain mitochondrial function.…”

Section: Mitochondrial Functionality In Ageing and Admentioning

confidence: 99%

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

Pallàs

2012

ISRN Cell Biology

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The causes of aging remain unknown, but they are probably intimately linked to a multifactorial process that affects cell networks to varying degrees. Although a growing number of aging and Alzheimer's disease (AD) animal models are available, a more comprehensive and physiological mouse model is required. In this context, the senescence-accelerated mouse prone 8 (SAMP8) has a number of advantages, since its rapid physiological senescence means that it has about half the normal lifespan of a rodent. In addition, according to data gathered over the last five years, some of its behavioral traits and histopathology resemble AD human dementia. SAMP8 has remarkable pathological similarities to AD and may prove to be an excellent model for acquiring more in-depth knowledge of the age-related neurodegenerative processes behind brain senescence and AD in particular. We review these facts and particularly the data on parameters related to neurodegeneration. SAMP8 also shows signs of aging in the immune, vascular, and metabolic systems, among others.

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Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease

Cited by 817 publications

References 95 publications

Mitochondria and aging: A role for the mitochondrial transition pore?

Mitochondria and aging: A role for the mitochondrial transition pore?

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

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