Neuroinflammation as a Common Feature of Neurodegenerative Disorders

Frontiers in Pharmacology, Journal Year: 2019, Volume and Issue: 10

Published: Sept. 12, 2019

Neurodegenerative diseases share the fact that they derive from altered proteins undergo an unfolding process followed by formation of -structures, and a pathological tendency to self-aggregate in neuronal cells. This is characteristic tau protein Alzheimer´s disease several tauopathies associated unfolding, synuclein Parkinson huntingtin Huntington disease. Usually self-aggregation products are toxic these cells, toxicity spreads all over different brain areas. We have postulated events molecular alterations trigger neurodegenerative disorders. Most interestingly, occur as result neuroinflammatory cascades involving cross-talks between glial cells neurons consequence activation microglia astrocytes. The model we hypothesized for disease, involve damage signals promote activation, NFβ synthesis release proinflammatory cytokines such TNF-, IL1, IL-6, IL-12 affects receptors with overactivation kinases. These patterns can be applied In this context, involvement innate immunity seems major paradigm pathogenesis diseases. important element search potential therapeutic approaches

Language: Английский

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Tau protein aggregation is associated with cellular senescence in the brain

Aging Cell, Journal Year: 2018, Volume and Issue: 17(6)

Published: Aug. 20, 2018

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), traumatic injury (TBI), and over twenty others. Tau-containing neurofibrillary tangle (NFT) closest correlate with cognitive decline cell loss (Arriagada, Growdon, Hedley-Whyte, & Hyman, ), yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis (de Calignon, Spires-Jones, Pitstick, Carlson, 2009), which suggests that secondary driving toxicity. Transcriptomic analyses of NFT-containing neurons microdissected from postmortem AD revealed an expression profile consistent cellular senescence. This complex stress response induces aberrant cycle activity, adaptations to maintain survival, remodeling, metabolic dysfunction. Using four transgenic mouse models, we found NFTs, but Aβ plaques, display a senescence-like phenotype. Cdkn2a transcript level, hallmark measure senescence, directly correlated atrophy burden in mice. relationship extended tissue humans PSP indicate phenomenon mice late-stage were treated senolytics remove senescent cells. Despite advanced age progression, MRI imaging histopathological indicated reduction total density, neuron loss, ventricular enlargement. Collectively, these findings strong association between presence NFTs senescence brain, contributes neurodegeneration. Given prevalence deposition neurodegenerative have broad implications for understanding, potentially treating, dozens diseases.

Language: Английский

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Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 72, P. 101496 - 101496

Published: Oct. 22, 2021

Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.

Language: Английский

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Cellular Senescence in Brain Aging

Frontiers in Aging Neuroscience, Journal Year: 2021, Volume and Issue: 13

Published: Feb. 25, 2021

Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in structural plasticity dendritic spines. Decreased number maturity spines aged animals humans, together synaptic transmission, may reflect aberrant neuronal directly associated impaired functions. In extreme, neurodegenerative disease, completely devastates basic functions brain, develop. While cellular senescence peripheral tissues recently linked aging aging-related disorders, its involvement is just beginning be explored. However, accumulated evidence suggests that cell play role it documented other organs. Senescent cells stop dividing shift their activity strengthen secretory function, leads acquisition so called senescence-associated phenotype (SASP). have also characteristics, such altered morphology proteostasis, decreased propensity undergo apoptosis, autophagy impairment, accumulation lipid droplets, increased senescence-associated-β-galactosidase (SA-β-gal), epigenetic alterations, including DNA methylation, chromatin remodeling, histone post-translational modifications that, consequence, result gene expression. Proliferation-competent glial both vitro vivo , they likely participate neuroinflammation, characteristic for brain. apart from proliferation-competent cells, consists post-mitotic neurons. Interestingly, emerged recently, non-proliferating present or cultivated some hallmarks, SASP, typical senescent ceased divide. It senolytics, by definition, eliminate improve ability mice models. this review, we ask questions about impairments how senolytics them. We will discuss whether plasticity, defined morphological functional at level neurons spines, hallmark susceptible effects senolytics.

Language: Английский

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Functional connectivity associated with tau levels in ageing, Alzheimer’s, and small vessel disease

Brain, Journal Year: 2019, Volume and Issue: 142(4), P. 1093 - 1107

Published: Feb. 4, 2019

In Alzheimer's disease, tau pathology spreads hierarchically from the inferior temporal lobe throughout cortex, ensuing cognitive decline and dementia. Similarly, circumscribed patterns of pathological have been observed in normal ageing small vessel suggesting a spatially ordered distribution across different diseases. vitro findings suggest that may spread 'prion-like' neuronal connections an activity-dependent manner. Supporting this notion, functional brain networks show spatial correspondence to deposition patterns. However, it remains unclear whether higher network-connectivity facilitates propagation. To address this, we included 55 aged elderly (i.e. cognitively normal, amyloid-negative), 50 disease patients amyloid-positive) covering preclinical dementia spectrum, as well 36 with pure amyloid-negative) vascular impairment due disease. All subjects were assessed AV1451 tau-PET resting-state MRI. Within each group, computed atlas-based MRI connectivity 400 regions interest entire neocortex. Using same atlas, also within group covariance levels among interest. We found between any given region pair was associated binding corresponding This result consistently ageing, impairment. particular, tau-hotspots, defined by highest uptake, showed high predictive value functionally closely connected These associations uptake detected regardless presence symptoms (mild or dementia), amyloid (as amyloid-PET) Our is shared tau-levels, supporting view prion-like spreading facilitated neural activity.

Language: Английский

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Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12841 - 12841

Published: Oct. 25, 2022

Alzheimer’s disease (AD) is the leading cause of dementia in elderly people. Amyloid beta (Aβ) deposits and neurofibrillary tangles are major pathological features an brain. These proteins highly expressed nerve cells found most tissues. Tau primarily provides stabilization to microtubules part axons dendrites. However, tau a state becomes hyperphosphorylated, causing dysfunction synaptic impairment degeneration neurons. This article presents summary role tau, phosphorylated (p-tau) AD, other tauopathies. Tauopathies, including Pick’s disease, frontotemporal dementia, corticobasal degeneration, argyrophilic grain progressive supranuclear palsy, Huntington’s result misprocessing accumulation within neuronal glial cells. also focuses on current research post-translational modifications genetics pathology, tauopathies development new drugs targeting p-tau, therapeutics for treating possibly preventing

Language: Английский

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Tau aggregates are RNA-protein assemblies that mislocalize multiple nuclear speckle components

Neuron, Journal Year: 2021, Volume and Issue: 109(10), P. 1675 - 1691.e9

Published: April 13, 2021

Language: Английский

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Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology

Nature Aging, Journal Year: 2021, Volume and Issue: 1(12), P. 1107 - 1116

Published: Dec. 10, 2021

Language: Английский

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Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

Frontiers in Synaptic Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: March 9, 2023

The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, loss is, to date, one of the main biological correlates cognitive decline disease. This occurs prior neuronal with ample evidence that synaptic dysfunction precedes this, in support idea failure is crucial stage disease pathogenesis. two pathological hallmarks abnormal aggregates amyloid or tau proteins, have had demonstrable effects on physiology animal cellular models There also growing these proteins may synergistic effect neurophysiological dysfunction. Here, we review some findings alterations what know from models. First, briefly summarize human suggest synapses are altered, including how this relates network activity. Subsequently, considered, highlighting mouse pathology role play dysfunction, either isolation examining pathologies interact specifically focuses function observed models, typically measured using electrophysiology calcium imaging. Following loss, it would be impossible imagine not alter oscillatory activity brain. Therefore, discusses underpin aberrant patterns seen patients. Finally, an overview key directions considerations field covered. includes current therapeutics targeted at but methods modulate rescue patterns. Other important future avenues note include non-neuronal cell types such as astrocytes microglia, mechanisms independent will certainly continue for foreseeable future.

Language: Английский

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Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses

Aging and Disease, Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 8, 2023

Alzheimer's disease (AD) is a prevalent neurodegenerative characterized by both amnestic and non-amnestic clinical manifestations. It accounts for approximately 60-70% of all dementia cases worldwide. With the increasing number AD patients, elucidating underlying mechanisms developing corresponding interventional strategies are necessary. Hypotheses about such as amyloid cascade, Tau hyper-phosphorylation, neuroinflammation, oxidative stress, mitochondrial dysfunction, cholinergic, vascular hypotheses not mutually exclusive, them play certain role in development AD. The cascade hypothesis currently most widely studied; however, other also gaining support. This article summarizes recent evidence regarding major pathological their potential interplay, well strengths weaknesses each implications effective treatments. could stimulate further studies promote more therapeutic

Language: Английский

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