Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease

Molecular Neurodegeneration, Journal Year: 2020, Volume and Issue: 15(1)

Published: July 16, 2020

Abstract Alzheimer’s disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There currently no effective treatment for AD, which may be attributed part to lack of a clear underlying mechanism. Studies within last few decades provide growing evidence central role amyloid β (Aβ) and tau, as well glial contributions various molecular cellular pathways AD pathogenesis. Herein, we review recent progress with respect Aβ- tau-associated mechanisms, discuss dysfunction emphasis on neuronal receptors that mediate Aβ-induced toxicity. We also other critical factors affect pathogenesis, including genetics, aging, variables related environment, lifestyle habits, describe potential apolipoprotein E (APOE), viral bacterial infection, sleep, microbiota. Although have gained much towards understanding aspects this devastating disorder, greater commitment research mechanism, diagnostics will needed future research.

Language: Английский

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Glymphatic System Impairment in Alzheimer’s Disease and Idiopathic Normal Pressure Hydrocephalus

Trends in Molecular Medicine, Journal Year: 2020, Volume and Issue: 26(3), P. 285 - 295

Published: Jan. 18, 2020

Language: Английский

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Glymphatic system impairment in multiple sclerosis: relation with brain damage and disability

Brain, Journal Year: 2021, Volume and Issue: 145(8), P. 2785 - 2795

Published: Dec. 13, 2021

Recent evidence has shown the existence of a CNS 'waste clearance' system, defined as glymphatic system. Glymphatic abnormalities have been described in several neurodegenerative conditions, including Alzheimer's and Parkinson's disease. function not thoroughly explored multiple sclerosis, where processes are intermingled with inflammatory processes. We aimed to investigate system sclerosis evaluate its association clinical disability, disease course, demyelination neurodegeneration, quantified using different MRI techniques. In this retrospective study, we enrolled 71 patients (49 relapsing-remitting 22 progressive sclerosis) 32 age- sex-matched healthy control subjects. All subjects underwent neurological assessment high-resolution T1, T2 double inversion recovery sequences, diffusion susceptibility weighted imaging. calculated along perivascular space index, proxy for function, cortical deep grey matter volume, white lesion volume normal-appearing microstructural damage. Multiple showed an overall lower index versus controls (estimated mean difference: -0.09, P = 0.01). Both had -0.06, 0.04 -0.19, 0.001 patients). Progressive 0.03). patients, was associated more severe disability (r -0.45, 0.001) longer duration -0.37, 0.002). Interestingly, detected negative between first 4.13 years course -0.38, 0.04) without any thereafter (up 34 duration). Lower higher -0.36, 0.003) -0.41, 0.30, 0.007) 0.42, atrophy, reduced fractional anisotropy increased diffusivity matter. Our results suggest that is impaired especially stages. Impaired measures both neurodegeneration reflects disability. These findings impairment may be pathological mechanism underpinning sclerosis. The dynamic interplay other substrates deserves further investigation.

Language: Английский

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Choroid plexus enlargement is associated with neuroinflammation and reduction of blood brain barrier permeability in depression

NeuroImage Clinical, Journal Year: 2021, Volume and Issue: 33, P. 102926 - 102926

Published: Dec. 27, 2021

Recent studies have shown that choroid plexuses (CP) may be involved in the neuro-immune axes, playing a role interaction between central and peripheral inflammation. Here we aimed to investigate CP volume alterations depression their associations with inflammation.51 depressed participants (HDRS score > 13) 25 age- sex-matched healthy controls (HCs) from Wellcome Trust NIMA consortium were re-analysed for study. All underwent full cytokine profiling simultaneous [11C]PK11195 PET/structural MRI imaging measuring neuroinflammation respectively.We found significantly greater subjects compared HCs (t(76) = +2.17) was positively correlated PET binding anterior cingulate cortex (r 0.28, p 0.02), prefrontal 0.24, 0.04), insular but not inflammatory markers: CRP levels 0.07, 0.53), IL-6 -0.08, 0.61), TNF-α -0.06, 0.70). The 0.34, 0.005). Integration of transcriptomic data Allen Human Brain Atlas brain map depicting correlations significant gene enrichment several pathways neuroinflammatory response.This result supports hypothesis changes barriers cause reduction solute exchanges blood CSF, disturbing homeostasis ultimately contributing inflammation depression. Given anomalies been recently detected other disorders, these results specific might extend conditions component.

Language: Английский

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Decreased CSF clearance and increased brain amyloid in Alzheimer’s disease

Fluids and Barriers of the CNS, Journal Year: 2022, Volume and Issue: 19(1)

Published: March 14, 2022

Abstract Background In sporadic Alzheimer’s disease (AD), brain amyloid-beta (Aβ) deposition is believed to be a consequence of impaired Aβ clearance, but this relationship not well established in living humans. CSF major feature glymphatic clearance (BGC), has been shown abnormal AD murine models. MRI phase contrast and intrathecally delivered studies have reported reduced flow AD. Using PET tau tracer 18 F-THK5117, we previously that the ventricular was associated with elevated levels. Methods present study, use two tracers, F-THK5351 11 C-PiB estimate calculated from early dynamic frames 9 normal controls 15 participants. Results observed measures were correlated (r = 0.66, p < 0.01), reductions 27%, respectively. We also replicated significant between ( F-THK5351) load − 0.64, n 24, 0.01). With larger sample size, extended our observations show cortical thickness cognitive performance. Conclusions Overall, findings support hypothesis failed related pathology Longitudinal are needed determine whether predictor progressive amyloidosis or its consequence.

Language: Английский

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Perivascular spaces and their role in neuroinflammation

Neuron, Journal Year: 2022, Volume and Issue: 110(21), P. 3566 - 3581

Published: Nov. 1, 2022

Language: Английский

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Roles of Ependymal Cells in the Physiology and Pathology of the Central Nervous System

Aging and Disease, Journal Year: 2022, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2022

Ependymal cells are indispensable components of the central nervous system (CNS). They originate from neuroepithelial neural plate and show heterogeneity, with at least three types that localized in different locations CNS. As glial CNS, accumulating evidence demonstrates ependymal play key roles mammalian CNS development normal physiological processes by controlling production flow cerebrospinal fluid (CSF), brain metabolism, waste clearance. have been attached to great importance neuroscientists because their potential participate disease progression. Recent studies demonstrated progression various neurological diseases, such as spinal cord injury hydrocephalus, raising possibility they may serve a therapeutic target for disease. This review focuses on function developmental well after discusses underlying mechanisms functions cells.

Language: Английский

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Sickness behaviour and depression: An updated model of peripheral-central immunity interactions

Brain Behavior and Immunity, Journal Year: 2023, Volume and Issue: 111, P. 202 - 210

Published: April 17, 2023

Current research into mood disorders indicates that circulating immune mediators participating in the pathophysiology of chronic somatic have potent influences on brain function. This paradigm has brought to fore use anti-inflammatory therapies as adjunctive standard antidepressant therapy improve treatment efficacy, particularly subjects do not respond medication. Such new practice requires biomarkers tailor these those most likely benefit but also validated mechanisms action describing interaction between peripheral immunity and function optimize target intervention. These are generally studied preclinical models try recapitulate human disease, MDD, through peripherally induced sickness behaviour. In this proposal paper, after an appraisal data rodent their adherence clinical cohorts, we put forward a modified model periphery-brain interactions goes beyond currently established view microglia cells drivers depression. Instead, suggest that, for patients with mild levels inflammation, barriers primary actors disease resistance. We then highlight gaps novel lines research.

Language: Английский

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Glymphatic clearance estimated using diffusion tensor imaging along perivascular spaces is reduced after traumatic brain injury and correlates with plasma neurofilament light, a biomarker of injury severity

Brain Communications, Journal Year: 2023, Volume and Issue: 5(3)

Published: Jan. 1, 2023

Abstract The glymphatic system is a perivascular fluid clearance system, most active during sleep, considered important for clearing the brain of waste products and toxins. Glymphatic failure hypothesized to underlie protein deposition in neurodegenerative disorders like Alzheimer’s disease. Preclinical evidence suggests that functioning also essential recovery from traumatic injury, which involves release debris toxic proteins need be cleared brain. In cross-sectional observational study, we estimated using diffusion tensor imaging along spaces, an MRI-derived measure water diffusivity surrounding veins periventricular region, 13 non-injured controls 37 subjects who had experienced injury ∼5 months previously. We additionally measured volume space T2-weighted MRI. plasma concentrations neurofilament light chain, biomarker severity, subset subjects. Diffusion spaces index was modestly though significantly lower with compared when covarying age. significantly, negatively correlated blood levels chain. Perivascular did not differ as correlate suggesting it may less sensitive injury-related changes. impairment after could due mechanisms such mislocalization channels, inflammation, proteinopathy and/or sleep disruption. promising method estimating clearance, additional work needed confirm results assess associations outcome. Understanding changes following inform novel therapies improve short-term reduce later risk neurodegeneration.

Language: Английский

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Cognitive Impairment Is Related to Glymphatic System Dysfunction in Pediatric Multiple Sclerosis

Annals of Neurology, Journal Year: 2024, Volume and Issue: 95(6), P. 1080 - 1092

Published: March 13, 2024

Objective The aim of this study was to investigate whether, compared pediatric healthy controls (HCs), the glymphatic system is impaired in multiple sclerosis (MS) patients according their cognitive status, and assess its association with clinical disability MRI measures brain structural damage. Method s Sixty‐five MS (females = 62%; median age 15.5 [interquartile range, IQR 14.5;17.0] years) 23 age‐ sex‐matched HCs 44%; 14.1 [IQR 11.8;16.2] underwent neurological, neuropsychological 3.0 Tesla assessment, including conventional diffusion tensor imaging (DTI). We calculated along perivascular space (DTI‐ALPS) index, a proxy function. Cognitive impairment (Co‐I) defined as at least 2 domains. Results No significant differences DTI‐ALPS index were found between cognitively preserved (Co‐P) (estimated mean difference [EMD] −0.002 [95% confidence interval −0.069; 0.065], FDR‐p 0.956). Compared Co‐P patients, Co‐I (n 20) showed significantly lower (EMD −0.136 −0.214; −0.058], ≤ 0.004). In HCs, no associations observed normalized brain, cortical thalamic volumes, normal‐appearing white matter (NAWM) fractional anisotropy (FA) diffusivity (MD) (FDR‐p ≥ 0.348). higher WM lesion volume (LV), NAWM MD, volume, FA associated 0.016). Random Forest selected (relative importance [RI] 100%), LV (RI 59.5%) MD 57.1%) intelligence quotient 51.3%) informative predictors (out‐of‐bag area under curve 0.762). Interpretation Glymphatic dysfunction occurs MS, focal lesions, irreversible tissue loss accumulation impairment. ANN NEUROL 2024;95:1080–1092

Language: Английский

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