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Mitochondria and antioxidant targeted therapeutic strategies for Alzheimer's disease.

ABSTRACT: Oxidative stress and mitochondrial dysfunction are important features present in Alzheimer's disease (AD). They appear early and contribute to disease progression, both in human postmortem AD brains as well as in transgenic AD mouse brains. For this reason, targeting oxidative stress and mitochondria in AD may lead to the development of promising therapeutic strategies. Several exogenous antioxidant compounds have been tested and found beneficial in transgenic AD mice, such as vitamins and spices. However, their efficacy was much more modest in human trials. More recently, new strategies have been elaborated to promote endogenous antioxidant systems. Different pathways involved in oxidative stress response have been identified. Compounds able to upregulate these pathways are being generated and tested in animal models of AD and in human patients. Upregulation of antioxidant gene expression was beneficial in mice, giving hope for future avenues in the treatment of AD and other neurodegenerative disorders.

SUBMITTER: Dumont M

PROVIDER: S-EPMC3098571 | biostudies-other | 2010

REPOSITORIES: biostudies-other

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Mitochondria and antioxidant targeted therapeutic strategies for Alzheimer's disease.

Dumont Magali M Lin Michael T MT Beal M Flint MF

Journal of Alzheimer's disease : JAD 20100101

Oxidative stress and mitochondrial dysfunction are important features present in Alzheimer's disease (AD). They appear early and contribute to disease progression, both in human postmortem AD brains as well as in transgenic AD mouse brains. For this reason, targeting oxidative stress and mitochondria in AD may lead to the development of promising therapeutic strategies. Several exogenous antioxidant compounds have been tested and found beneficial in transgenic AD mice, such as vitamins and spice ...[more]

PMID: 20421689

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Project description:Alzheimer's disease (AD) is the most common type of dementia, with increasing prevalence and no disease-modifying treatment available yet. There is increasing evidence-from interventions targeting mitochondria-that may shed some light on new strategies for the treatment of AD. Previously, using senescence-accelerated OXYS rats that simulate key characteristics of sporadic AD, we have shown that treatment with mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) from age 12 to 18 months (that is, during active progression of AD-like pathology)-via improvement of mitochondrial function-prevented the neuronal loss and synaptic damage, enhanced neurotrophic supply, and decreased amyloid-β 1-42 protein levels and tau hyperphosphorylation in the hippocampus. In the present study, we continued to explore the mechanisms of the anti-AD effects of SkQ1 in an OXYS rat model through deep RNA sequencing (RNA-seq) and focused upon the cell-specific gene expression alterations in the hippocampus. According to RNA-seq results, OXYS rats had 1,159 differentially expressed genes (DEGs) relative to Wistar rats (control), and 6-month treatment with SkQ1 decreased their number twofold. We found that 10.5% of all DEGs in untreated (control) OXYS rats were associated with mitochondrial function, whereas SkQ1 eliminated differences in the expression of 76% of DEGs (93 from 122 genes). Using transcriptome approaches, we found that the anti-AD effects of SkQ1 are associated with an improvement of the activity of many signaling pathways and intracellular processes. SkQ1 changed the expression of genes in neuronal, glial, and endothelial cells, and these genes are related to mitochondrial function, neurotrophic and synaptic activity, calcium processes, immune and cerebrovascular systems, catabolism, degradation, and apoptosis. Thus, RNA-seq analysis yields a detailed picture of transcriptional changes during the development of AD-like pathology and can point to the molecular and genetic mechanisms of action of the agents (including SkQ1) holding promise for the prevention and treatment of AD.

Project description:Alzheimer's disease is a rather complex neurodegenerative disease, which is attributed to a combination of multiple factors. Among the many pathological pathways, synaptic dysfunctions, such as synapses loss and deficits in synaptic plasticity, were thought to be strongly associated with cognitive decline. The deficiencies in various sorts of neurotransmissions are responsible for the multifarious neurodegenerative symptoms in Alzheimer's disease, for example, the cholinergic and glutamatergic deficits for cognitive decline, the excitatory and inhibitory neurotransmission dyshomeostasis for synaptic plasticity deficits and epileptiform symptoms, and the monoamine neurotransmission for neuropsychiatric symptoms. Amyloid cascade hypothesis is the most popular pathological theory to explain Alzheimer's disease pathogenesis and attracts considerable attention. Multiple lines of genetic and pathological evidence support the predominant role of amyloid beta in Alzheimer's disease pathology. Neurofibrillary tangles assembled by microtubule-associated protein tau are other important histopathological characteristics in Alzheimer's disease brains. Cascade of tau toxicity was proved to lead to neuron damage, neuroinflammation and oxidative stress in brain. Ageing is the main risk factor of neurodegenerative diseases, and is associated with inflammation, oxidative stress, reduced metabolism, endocrine insufficiencies and organ failures. These aging related risk factors were also proved to be some of the risk factors contributing to Alzheimer's disease. In Alzheimer's disease drug development, many good therapeutic strategies have been investigated in clinical evaluations. However, complex mechanism of Alzheimer's disease and the interplay among different pathological factors call for the come out of all-powerful therapies with multiple curing functions. This review seeks to summarize some of the representative treatments targeting different pathological pathways currently under clinical evaluations. Multi-target therapies as an emerging strategy for Alzheimer's disease treatment will be highlighted.

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Mitochondria and antioxidant targeted therapeutic strategies for Alzheimer's disease.

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Mitochondria and antioxidant targeted therapeutic strategies for Alzheimer's disease.

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