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      Molecular Basis of Alzheimer’s Disease: Focus on Mitochondria

      1 , 1 , 2 , 3 , 4 , 5
      Journal of Alzheimer's Disease
      IOS Press

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          The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives.

          Ten years ago we first proposed the Alzheimer's disease (AD) mitochondrial cascade hypothesis. This hypothesis maintains that gene inheritance defines an individual's baseline mitochondrial function; inherited and environmental factors determine rates at which mitochondrial function changes over time; and baseline mitochondrial function and mitochondrial change rates influence AD chronology. Our hypothesis unequivocally states in sporadic, late-onset AD, mitochondrial function affects amyloid precursor protein (APP) expression, APP processing, or beta amyloid (Aβ) accumulation and argues if an amyloid cascade truly exists, mitochondrial function triggers it. We now review the state of the mitochondrial cascade hypothesis, and discuss it in the context of recent AD biomarker studies, diagnostic criteria, and clinical trials. Our hypothesis predicts that biomarker changes reflect brain aging, new AD definitions clinically stage brain aging, and removing brain Aβ at any point will marginally impact cognitive trajectories. Our hypothesis, therefore, offers unique perspective into what sporadic, late-onset AD is and how to best treat it.
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            Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model.

            Synaptic dysfunction and the loss of synapses are early pathological features of Alzheimer's disease (AD). Synapses are sites of high energy demand and extensive calcium fluctuations; accordingly, synaptic transmission requires high levels of ATP and constant calcium fluctuation. Thus, synaptic mitochondria are vital for maintenance of synaptic function and transmission through normal mitochondrial energy metabolism, distribution and trafficking, and through synaptic calcium modulation. To date, there has been no extensive analysis of alterations in synaptic mitochondria associated with amyloid pathology in an amyloid β (Aβ)-rich milieu. Here, we identified differences in mitochondrial properties and function of synaptic vs. nonsynaptic mitochondrial populations in the transgenic mouse brain, which overexpresses the human mutant form of amyloid precursor protein and Aβ. Compared with nonsynaptic mitochondria, synaptic mitochondria showed a greater degree of age-dependent accumulation of Aβ and mitochondrial alterations. The synaptic mitochondrial pool of Aβ was detected at an age as young as 4 mo, well before the onset of nonsynaptic mitochondrial and extensive extracellular Aβ accumulation. Aβ-insulted synaptic mitochondria revealed early deficits in mitochondrial function, as shown by increased mitochondrial permeability transition, decline in both respiratory function and activity of cytochrome c oxidase, and increased mitochondrial oxidative stress. Furthermore, a low concentration of Aβ (200 nM) significantly interfered with mitochondrial distribution and trafficking in axons. These results demonstrate that synaptic mitochondria, especially Aβ-rich synaptic mitochondria, are more susceptible to Aβ-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction relevant to the development of synaptic degeneration in AD.
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              Is Alzheimer's disease a Type 3 Diabetes? A critical appraisal.

              Recently researchers proposed the term 'Type-3-Diabetes' for Alzheimer's disease (ad) because of the shared molecular and cellular features among Type-1-Diabetes, Type-2-Diabetes and insulin resistance associated with memory deficits and cognitive decline in elderly individuals. Recent clinical and basic studies on patients with diabetes and AD revealed previously unreported cellular and pathological among diabetes, insulin resistance and AD. These studies are also strengthened by various basic biological studies that decipher the effects of insulin in the pathology of AD through cellular and molecular mechanisms. For instance, insulin is involved in the activation of glycogen synthase kinase 3β, which in turn causes phosphorylation of tau, which involved in the formation of neurofibrillary tangles. Interestingly, insulin also plays a crucial role in the formation amyloid plaques. In this review, we discussed significant shared mechanisms between AD and diabetes and we also provided therapeutic avenues for diabetes and AD. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.
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                Author and article information

                Journal
                Journal of Alzheimer's Disease
                JAD
                IOS Press
                13872877
                18758908
                March 22 2019
                March 22 2019
                : 1-22
                Affiliations
                [1 ]Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX, USA
                [2 ]Garrison Institute on Aging, South West Campus, Texas Tech University Health Sciences Center, Lubbock, TX, USA
                [3 ]Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, USA
                [4 ]Department of Pharmacology & Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, USA
                [5 ]Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
                Article
                10.3233/JAD-190048
                30932888
                06358e1f-e123-444e-ac68-03f8db56bbea
                © 2019
                History

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