The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

Acta Neuropathologica, Journal Year: 2020, Volume and Issue: 140(4), P. 417 - 447

Published: July 29, 2020

Abstract Tau and amyloid beta (Aβ) are the prime suspects for driving pathology in Alzheimer’s disease (AD) and, as such, have become focus of therapeutic development. Recent research, however, shows that these proteins been highly conserved throughout evolution may crucial, physiological roles. Such functions be lost during AD progression or unintentionally disrupted by tau- Aβ-targeting therapies. has revealed to more than a simple stabiliser microtubules, reported play role range biological processes including myelination, glucose metabolism, axonal transport, microtubule dynamics, iron homeostasis, neurogenesis, motor function, learning memory, neuronal excitability, DNA protection. Aβ is similarly multifunctional, proposed regulate angiogenesis, repair leaks blood–brain barrier, promote recovery from injury, act an antimicrobial peptide tumour suppressor. This review will discuss potential roles tau Aβ, highlighting how changes contribute pathology, well implications We propose balanced consideration both pathological essential design safe effective therapeutics.

Language: Английский

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The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: June 10, 2022

The NLRP3 inflammasome is a multiprotein complex that plays pivotal role in regulating the innate immune system and inflammatory signaling. Upon activation by PAMPs DAMPs, oligomerizes activates caspase-1 which initiates processing release of pro-inflammatory cytokines IL-1β IL-18. most extensively studied to date due its array activators aberrant several diseases. Studies using small molecules biologics targeting pathway have shown positive outcomes treating various disease pathologies blocking chronic inflammation. In this review, we discuss recent advances understanding mechanism, pathology, provide broad review therapeutics discovered target their challenges.

Language: Английский

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The synapse in traumatic brain injury

Brain, Journal Year: 2020, Volume and Issue: 144(1), P. 18 - 31

Published: Sept. 10, 2020

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide risk factor for dementia later in life. Research into the pathophysiology TBI has focused on impact neuron. However, recent advances have shown that major synapse structure function through combination immediate mechanical insult ensuing secondary processes, to loss. In this review, we highlight role with focus confluence multiple processes including excitotoxicity, inflammation oxidative stress. The primary triggers cascade events each these discuss complex interplay occurs at synapse. We also examine how impacted by traumatic axonal it may play spread tau after TBI. propose astrocytes crucial mediating both loss recovery. Finally, developments field molecular imaging, fluid biomarkers therapeutics. particular, our understanding diversity suggest new technology synaptome mapping prove useful identifying synapses are vulnerable or resistant

Language: Английский

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Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(10), P. 5404 - 5404

Published: May 12, 2022

Alzheimer's disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to discovery heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due repeated failure translational applications from animal models human patients, along with recent advances genetic susceptibility our current understanding on biology, these have evolved over time an attempt better reproduce complexity this devastating improve their applicability. In review, we provide a comprehensive overview about major pathological elements AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation glial dysfunction), discussing knowledge that available mouse provided mechanisms underlying disease. Moreover, highlight pros cons models, revolution offered by concomitant use omics technologies may lead more rapid improvement present battery.

Language: Английский

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Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 86, P. 101856 - 101856

Published: Jan. 19, 2023

Language: Английский

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Chronic effects of inflammation on tauopathies

The Lancet Neurology, Journal Year: 2023, Volume and Issue: 22(5), P. 430 - 442

Published: April 13, 2023

Language: Английский

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Extracellular cold-inducible RNA-binding protein in CNS injury: molecular insights and therapeutic approaches

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Jan. 21, 2025

Abstract Central nervous system (CNS) injuries, such as ischemic stroke (IS), intracerebral hemorrhage (ICH) and traumatic brain injury (TBI), are a significant global burden. The complex pathophysiology of CNS is comprised primary secondary injury. Inflammatory incited by damage-associated molecular patterns (DAMPs) which signal variety resident cells infiltrating immune cells. Extracellular cold-inducible RNA-binding protein (eCIRP) DAMP acts through multiple non-immune to promote inflammation. Despite the well-established role eCIRP in systemic sterile inflammation, its less elucidated. Recent literature suggests that pleiotropic inflammatory mediator also being evaluated clinical biomarker indicate prognosis injuries. This review provides broad overview injury, with focus on immune-mediated neuroinflammation. We then what known about mechanisms both non-CNS cells, identifying opportunities for further study. explore eCIRP’s potential prognostic marker severity outcome. Next, we provide an eCIRP-targeting therapeutics suggest strategies develop these agents ameliorate Finally, emphasize exploring novel mechanisms, aside from neuroinflammation, critical therapeutic target

Language: Английский

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The role of innate immunity in Alzheimer's disease

Immunological Reviews, Journal Year: 2020, Volume and Issue: 297(1), P. 225 - 246

Published: June 26, 2020

Abstract The amyloid hypothesis has dominated Alzheimer's disease (AD) research for almost 30 years. This hinges on the predominant clinical role of beta (Aβ) peptide in propagating neurofibrillary tangles (NFTs) and eventual cognitive impairment AD. Recent AD field identified brain‐resident macrophages, known as microglia, their receptors integral regulators both initiation propagation inflammation, Aβ accumulation, neuronal loss, memory decline Emerging studies have also begun to reveal critical roles distinct innate immune pathways pathogenesis, which led great interest harnessing response a therapeutic strategy treat In this review, we will highlight recent advancements our understanding immunity inflammation onset progression. Additionally, there been mounting evidence suggesting pivotal contributions environmental factors lifestyle choices pathogenesis. Therefore, discuss findings, that many these risk influence progression via modulation microglia responses.

Language: Английский

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Mechanosensation in traumatic brain injury

Neurobiology of Disease, Journal Year: 2020, Volume and Issue: 148, P. 105210 - 105210

Published: Nov. 28, 2020

Traumatic brain injury (TBI) is distinct from other neurological disorders because it induced by a discrete event that applies extreme mechanical forces to the brain. This review describes how senses, integrates, and responds under both normal conditions during injury. The response influenced unique properties of tissue, which differ region, cell type, sub-cellular structure. Elements such as extracellular matrix, plasma membrane, transmembrane receptors, cytoskeleton influence its properties. These same components also act force-sensors, allowing neurons glia respond their physical environment maintain homeostasis. However, when applied become too large, in TBI, these may an aberrant manner or structurally fail, resulting pathological sequelae. so-called "pathological mechanosensation" represents spectrum cellular responses, vary depending on overall biomechanical parameters be compounded repetitive injuries. Such responses and/or damage cells along with secondary cascades can ultimately lead long-term dysfunction degeneration, often persistent deficits. Indeed, mechanosensation not only directly initiates cascades, but this post-physical provides context unfold. Collectively, points underscore need use experimental models accurately replicate biomechanics TBI humans. Understanding uncover therapeutic targets addressing various facets trauma-specific

Language: Английский

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Post-Traumatic Epilepsy and Comorbidities: Advanced Models, Molecular Mechanisms, Biomarkers, and Novel Therapeutic Interventions

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 74(2), P. 387 - 438

Published: March 17, 2022

Post-traumatic epilepsy (PTE) is one of the most devastating long-term, network consequences traumatic brain injury (TBI). There currently no approved treatment that can prevent onset spontaneous seizures associated with injury, and many cases PTE are refractory to antiseizure medications. epileptogenesis an enduring process by which a normal exhibits hypersynchronous excitability after head incident. Understanding neural networks molecular pathologies involved in key preventing its development or modifying disease progression. In this article, we describe critical appraisal current state research emphasis on experimental models, mechanisms post-traumatic epileptogenesis, potential biomarkers, burden PTE-associated comorbidities. The goal identify new therapeutic strategies interrupt epileptogenic relieve neuropsychiatric Therefore, also preclinical clinical data sequelae. Differences patterns, latency period, biomarkers outlined context animal model validation, pathophysiology, seizure frequency, behavior. Improving TBI recovery complex challenging tasks; however, much progress has been made within decade demonstrating modifying, anti-inflammatory, neuroprotective strategies, suggesting pragmatic. Our understanding continuously evolving, improved models allow for accelerated testing critically needed novel interventions military civilian persons at high risk

Significance Statement

chronic condition injury. With few limited underlying progression extremely slow find preventative PTE. This study reviews modeling, pathology, There's optimism finding drug therapy people risk, such as concussion, serious injuries, especially persons.

Language: Английский

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