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Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications.

ABSTRACT: Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid ? (A?), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of A? is dysregulated, which leads to the accumulation and aggregation of A?. Metabolism of A? and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.

SUBMITTER: Uddin MS

PROVIDER: S-EPMC5797541 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications.

Uddin Md Sahab MS Stachowiak Anna A Mamun Abdullah Al AA Tzvetkov Nikolay T NT Takeda Shinya S Atanasov Atanas G AG Bergantin Leandro B LB Abdel-Daim Mohamed M MM Stankiewicz Adrian M AM

Frontiers in aging neuroscience 20180130

Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau prote ...[more]

PMID: 29441009

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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.

Dataset Information

Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications.

Publications

Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications.

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