The Association of Tau With Mitochondrial Dysfunction in Alzheimer's Disease

Cheng, Ying; Bai, Feng

doi:10.3389/fnins.2018.00163

Cited by 163 publications

(138 citation statements)

References 73 publications

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“…or neurofibrillary tangles even in the early stage of tau formation there may be impaired mitochondrial movement and repair i.e. hyperphosphorylated and aggregated tau appears to damage the axonal transport, leading to abnormal mitochondrial structural defects in synapses [116].…”

Section: Preprintsmentioning

confidence: 99%

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Hayden¹

2019

Preprint

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Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments associated with metabolic factors and increases the cellular vulnerability to develop the age-related increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.

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Section: Preprintsmentioning

confidence: 99%

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Hayden¹

2019

Preprint

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“…A Cyp-D deficiency can notably improve synaptic function and therefore improve learning and memory in an AD mouse model [107]. It was recently proposed that tau protein can regulate synaptic activity, affecting mitochondrial function and axonal transport [108], and post-transductionally modified tau can induce mitochondrial damage, leading to synaptic dysfunction [109]. In fact, hyper-phosphorylated tau impairs mitochondrial respiratory chain function, increases ROS levels, decreases the activity of detoxifying enzymes, and produces Δψm dissipation [108].…”

Section: Mitochondrial Dysfunction and Cognitive Impairmentmentioning

confidence: 99%

Mitochondrial Dysfunction as a Key Event during Aging: From Synaptic Failure to Memory Loss

Jara¹,

Torres²,

Olesen³

et al. 2020

Mitochondria and Brain Disorders

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Mitochondria are important cellular organelles with key regulatory functions in energy production, oxidative balance, and calcium homeostasis. This is especially important in the brain, since neurons require a large number of functional mitochondria to supply their high energy requirement, mainly for synaptic processes. A decrease in the activity and quality of mitochondria in the brain, particularly in the hippocampus, is associated with normal aging and a large number of neurodegenerative diseases compromising memory function. Although synaptic and cognitive dysfunction is multifactorial, growing evidence demonstrates that mitochondria play a key role in these processes and suggests that maintaining mitochondrial function could prevent these age-dependent alterations. In this chapter, we will discuss the hippocampal mitochondrial dysfunction present in aging and how these defects promote age-associated synaptic damage and cognitive impairment. We will summarize evidence that shows how neurodegeneration can be accelerated or attenuated during aging by modulating mitochondrial function.

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“…MT dysfunction can be due to hyperphosphorylated tau, which plays a pathological role, in addition to impairing axonal transport of organelles including mitochondria and results in synaptic dysfunction [73]. Tau, a major MT-associated protein, plays a consequential role in neuronal processes.…”

Section: Mitochondrial Dysfunction and Tau Hyperphosphorylationmentioning

confidence: 99%

“…It was filamentous, rather than soluble, forms of hyperphosphorylated tau that inhibited anterograde fast axonal transport by activating GSK-3 and axonal protein phosphatase. Defects in mitochondrial function are manifested by a variety of indicators, including decreased ATP synthesis, increased ROS production, impaired oxidative phosphorylation system complexes and antioxidant enzymes [73]. An inhibition of oxidative phosphorylation depolarizes mitochondria, which further impairs the ability of cells to buffer calcium loads.…”

Section: Mitochondrial Dysfunction and Tau Hyperphosphorylationmentioning

confidence: 99%

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

Duggal

Mehan

2019

ADR

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Neuronal microtubule (MT) tau protein provides cytoskeleton to neuronal cells and plays a vital role including maintenance of cell shape, intracellular transport, and cell division. Tau hyperphosphorylation mediates MT destabilization resulting in axonopathy and neurotransmitter deficit, and ultimately causing Alzheimer's disease (AD), a dementing disorder affecting vast geriatric populations worldwide, characterized by the existence of extracellular amyloid plaques and intracellular neurofibrillary tangles in a hyperphosphorylated state. Pre-clinically, streptozotocin stereotaxically mimics the behavioral and biochemical alterations similar to AD associated with tau pathology resulting in MT assembly defects, which proceed neuropathological cascades. Accessible interventions like cholinesterase inhibitors and NMDA antagonist clinically provides only symptomatic relief. Involvement of microtubule stabilizers (MTS) prevents tauopathy particularly by targeting MT oriented cytoskeleton and promotes polymerization of tubulin protein. Multiple in vitro and in vivo research studies have shown that MTS can hold substantial potential for the treatment of AD-related tauopathy dementias through restoration of tau function and axonal transport. Moreover, anti-cancer taxane derivatives and epothiolones may have potential to ameliorate MT destabilization and prevent the neuronal structural and functional alterations associated with tauopathies. Therefore, this current review strictly focuses on exploration of various clinical and pre-clinical features available for AD to understand the neuropathological mechanisms as well as introduce pharmacological interventions associated with MT stabilization. MTS from diverse natural sources continue to be of value in the treatment of cancer, suggesting that these agents have potential to be of interest in the treatment of AD-related tauopathy dementia in the future.

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The Association of Tau With Mitochondrial Dysfunction in Alzheimer's Disease

Cited by 163 publications

References 73 publications

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer’s Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy

Mitochondrial Dysfunction as a Key Event during Aging: From Synaptic Failure to Memory Loss

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

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