Amyloid precursor protein processing and bioenergetics

Wilkins, Heather; Swerdlow, Russell H.

doi:10.1016/j.brainresbull.2016.08.009

Cited by 151 publications

(105 citation statements)

References 132 publications

(153 reference statements)

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“…Histological hallmarks include hippocampal neuronal death, extracellular amyloid-β peptide deposition, and intracellular tau protein neurofibrillary tangles. Defects in mitochondrial and respiratory chain function may alter amyloid precursor protein (APP) processing, resulting in pathogenic amyloid-β fragment production [92]. Progressive cognitive degeneration in patients with AD has been linked to reduced uptake and metabolism of glucose [93].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Ketogenic Diets for Adult Neurological Disorders

McDonald

Cervenka

2018

Neurotherapeutics

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The current review highlights the evidence supporting the use of ketogenic diet therapies in the management of a growing number of neurological disorders in adults. An overview of the scientific literature supporting posited mechanisms of therapeutic efficacy is presented including effects on neurotransmission, oxidative stress, and neuro-inflammation. The clinical evidence supporting ketogenic diet use in the management of adult epilepsy, malignant glioma, Alzheimer's disease, migraine headache, motor neuron disease, and other neurologic disorders is highlighted and reviewed. Lastly, common adverse effects of ketogenic therapy in adults, including gastrointestinal symptoms, weight loss, and transient dyslipidemia are discussed.

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Section: Alzheimer's Diseasementioning

confidence: 99%

Ketogenic Diets for Adult Neurological Disorders

McDonald

Cervenka

2018

Neurotherapeutics

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“…The impaired glucose utilization may result, in part, from an adverse effect of Aβ on glucose transport into neurons because the oxidative stress caused by Aβ can impair function of the neuronal glucose transporter GLUT3 [130]. On the other hand, impaired mitochondrial function can accelerate the latter age-related alterations in neurons, and may also cause amyloidogenic processing of APP [131] and accumulation of hyperphosphorylated Tau in neurons [132]. Membrane lipid peroxidation resulting from mitochondria- and Aβ-derived ROS generates the aldehyde 4-hydroxynonenal which can promote amyloidogenic APP processing and the accumulation of pTau either by direct modification of APP secretase complex proteins and Tau or, indirectly by disrupting cellular Ca 2+ regulation and mitochondrial function [13, 122, 133, 134].…”

Section: Involvement Of Neuronal Mitochondria In Acute Brain Injuriesmentioning

confidence: 99%

Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance

Raefsky

Mattson

2017

Free Radical Biology and Medicine

193

123

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An important concept in neurobiology is “neurons that fire together, wire together” which means that the formation and maintenance of synapses is promoted by activation of those synapses. Very similar to the effects of the stress of exercise on muscle cells, emerging findings suggest that neurons respond to activity by activating signaling pathways (e.g., Ca2+, CREB, PGC-1α, NF-κB) that stimulate mitochondrial biogenesis and cellular stress resistance. These pathways are also activated by aerobic exercise and food deprivation, two bioenergetic challenges of fundamental importance in the evolution of the brains of all mammals, including humans. The metabolic ‘switch’ in fuel source from liver glycogen store-derived glucose to adipose cell-derived fatty acids and their ketone metabolites during fasting and sustained exercise, appears to be a pivotal trigger of both brain-intrinsic and peripheral organ-derived signals that enhance learning and memory and underlying synaptic plasticity and neurogenesis. Brain-intrinsic extracellular signals include the excitatory neurotransmitter glutamate and the neurotrophic factor BDNF, and peripheral signals may include the liver-derived ketone 3-hydroxybutyrate and the muscle cell-derived protein irisin. Emerging findings suggest that fasting, exercise and an intellectually challenging lifestyle can protect neurons against the dysfunction and degeneration that they would otherwise suffer in acute brain injuries (stroke and head trauma) and neurodegenerative disorders including Alzheimer’s, Parkinson’s and Huntington’s disease. Among the prominent intracellular responses of neurons to these bioenergetic challenges are up-regulation of antioxidant defenses, autophagy/mitophagy and DNA repair. A better understanding of such fundamental hormesis-based adaptive neuronal response mechanisms is expected to result in the development and implementation of novel interventions to promote optimal brain function and healthy brain aging.

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“…When APP reaches the cell surface, it may be further cleaved by different processing pathways, depending on its trafficking and localization ( Figure 1) [19]. It has been shown that APP residing at the cell surface is mainly cleaved by α-secretases that are also enriched at the cell membrane [20]. APP may also be internalized again to the endosome and encounter β-secretases, thereby initiating the amyloidogenic processing pathway [20].…”

Section: App Processingmentioning

confidence: 99%

“…It has been shown that APP residing at the cell surface is mainly cleaved by α-secretases that are also enriched at the cell membrane [20]. APP may also be internalized again to the endosome and encounter β-secretases, thereby initiating the amyloidogenic processing pathway [20]. The proteolytic cleavage of the amyloid precursor protein (APP) by the non-amyloidogenic (left) and amyloidogenic (right) processing pathways.…”

Section: App Processingmentioning

confidence: 99%

Phosphorylation Signaling in APP Processing in Alzheimer’s Disease

Zhang

Chen

Lee

2019

IJMS

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The abnormal accumulation of amyloid-β (Aβ) in the central nervous system is a hallmark of Alzheimer's disease (AD). The regulation of the processing of the single-transmembrane amyloid precursor protein (APP) plays an important role in the generation of Aβ in the brain. The phosphorylation of APP and key enzymes involved in the proteolytic processing of APP has been demonstrated to be critical for modulating the generation of Aβ by either altering the subcellular localization of APP or changing the enzymatic activities of the secretases responsible for APP processing. In addition, the phosphorylation may also have an impact on the physiological function of these proteins. In this review, we summarize the kinases and signaling pathways that may participate in regulating the phosphorylation of APP and secretases and how this further affects the function and processing of APP and Aβ pathology. We also discuss the potential of approaches that modulate these phosphorylation-signaling pathways or kinases as interventions for AD pathology.

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Amyloid precursor protein processing and bioenergetics

Cited by 151 publications

References 132 publications

Ketogenic Diets for Adult Neurological Disorders

Ketogenic Diets for Adult Neurological Disorders

Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance

Phosphorylation Signaling in APP Processing in Alzheimer’s Disease

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