Updates on the association of brain injury and Alzheimer's disease

Klomparens, Kara; Ding, Yuchuan

doi:10.4103/bc.bc_18_20

Cited by 8 publications

(2 citation statements)

References 20 publications

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“…Further to this, in patients with traumatic brain injury (TBI), nitrogen oxide (NOX) activity is elevated as early as one-hour post-injury, suggesting a pathological role of ROS in the outcomes of TBI (Zhang et al, 2012); the extent of ROS-associated tissue damage and mitochondrial dysfunction in TBI patients correlates with more severe outcomes (Tavazzi et al, 2005, Valko et al, 2007. This increase in ROS following brain injury may trigger degenerative signalling pathways, predisposing individuals to AD and other neurodegenerative conditions (Breunig et al, 2013, Klomparens and Ding, 2020, Mendez, 2017.…”

Section: Phenotypic Hallmarks Of Neuronal Ageing Are Increased By Oxi...mentioning

confidence: 99%

Oxidative stress promotes axonal atrophy through alterations in microtubules and EB1 function

Shields,

Wilkes,

Gozes

et al. 2024

Preprint

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Axons are crucial for transmitting neurochemical signals. As organisms age, the ability of neurons to maintain their axons declines; hence aged axons are more susceptible to damage or dysfunction. Understanding what causes axonal vulnerability is crucial for developing strategies to enhance overall resilience of neurons, and to prevent their deterioration during ageing or in age-related neurodegenerative diseases.Increasing levels of reactive oxygen species (ROS) causes oxidative stress, a hallmark of ageing and age-related diseases. Despite this association, a causal relationship between oxidative stress and neuronal ageing remains unclear, particularly how subcellular physiology is affected by ROS.By usingDrosophila-derived primary neuronal cultures and a recently developedin vivoneuronal model of ageing, which involves the visualisation ofDrosophilamedulla neurons, we investigated the interplay between oxidative stress, neuronal ageing and the microtubule cytoskeleton. We find that oxidative stress as a key driver of axonal and synaptic decay, including the appearance of axonal swellings, microtubule alterations in both axons and synapses and the morphological transformation of axonal terminals during ageing. We demonstrate that increased ROS sensitises the microtubule plus end binding factor, end-binding protein 1 (EB1), leading to microtubule defects, affecting neuronal integrity. Furthermore, manipulating EB1 proved to be a valuable therapeutic strategy to prevent ageing hallmarks observed in conditions of elevated ROS. In summary, we demonstrate a mechanistic pathway linking cellular oxidative stress, the microtubule cytoskeleton and axonal deterioration during ageing and provide evidence of the therapeutic potential of enhancing microtubule plus end physiology to improve the resilience of axons.

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Section: Phenotypic Hallmarks Of Neuronal Ageing Are Increased By Oxi...mentioning

confidence: 99%

Oxidative stress promotes axonal atrophy through alterations in microtubules and EB1 function

Shields,

Wilkes,

Gozes

et al. 2024

Preprint

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show abstract

“…Over time, mortality in patients with dementia remained increased [ 8 ]. Even though stroke and late-onset AD/ADRD are interrelated common comorbidities in the same aging/aged individuals [ 7 , 9 , 10 ], the pathophysiology associated with different time courses of disease development and their destructive impacts on each other are not explicitly understood. Historically and currently, stroke and AD have been investigated in separate research fields and are regarded as distinct acute and chronic brain disorders, respectively.…”

Section: Introductionmentioning

confidence: 99%

Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer’s disease

Jiang

Shim

et al. 2023

Mol Neurodegeneration

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Stroke and late-onset Alzheimer’s disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity and NMDAR-mediated Ca2+ influx are essential for neuronal function and cell survival. An ischemic insult, however, can cause rapid increases in glutamate concentration and excessive activation of NMDARs, leading to swift Ca2+ overload in neuronal cells and acute excitotoxicity within hours and days. On the other hand, mild upregulation of NMDAR activity, commonly seen in AD animal models and patients, is not immediately cytotoxic. Sustained NMDAR hyperactivity and Ca2+ dysregulation lasting from months to years, nevertheless, can be pathogenic for slowly evolving events, i.e. degenerative excitotoxicity, in the development of AD/ADRD. Specifically, Ca2+ influx mediated by extrasynaptic NMDARs (eNMDARs) and a downstream pathway mediated by transient receptor potential cation channel subfamily M member (TRPM) are primarily responsible for excitotoxicity. On the other hand, the NMDAR subunit GluN3A plays a “gatekeeper” role in NMDAR activity and a neuroprotective role against both acute and chronic excitotoxicity. Thus, ischemic stroke and AD share an NMDAR- and Ca2+-mediated pathogenic mechanism that provides a common receptor target for preventive and possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs and was approved by the Federal Drug Administration (FDA) for symptomatic treatment of moderate-to-severe AD with variable efficacy. According to the pathogenic role of eNMDARs, it is conceivable that MEM and other eNMDAR antagonists should be administered much earlier, preferably during the presymptomatic phases of AD/ADRD. This anti-AD treatment could simultaneously serve as a preconditioning strategy against stroke that attacks ≥ 50% of AD patients. Future research on the regulation of NMDARs, enduring control of eNMDARs, Ca2+ homeostasis, and downstream events will provide a promising opportunity to understand and treat the comorbidity of AD/ADRD and stroke.

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Transient Receptor Potential Mucolipin-1 Participates in Intracerebral Hemorrhage-Induced Secondary Brain Injury by Inducing Neuroinflammation and Neuronal Cell Death

Shi

Ding

et al. 2023

Neuromol Med

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Updates on the association of brain injury and Alzheimer's disease

Cited by 8 publications

References 20 publications

Oxidative stress promotes axonal atrophy through alterations in microtubules and EB1 function

Oxidative stress promotes axonal atrophy through alterations in microtubules and EB1 function

Extrasynaptic NMDA receptors in acute and chronic excitotoxicity: implications for preventive treatments of ischemic stroke and late-onset Alzheimer’s disease

Transient Receptor Potential Mucolipin-1 Participates in Intracerebral Hemorrhage-Induced Secondary Brain Injury by Inducing Neuroinflammation and Neuronal Cell Death

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