Cognitive impact of COVID-19: looking beyond the short term

Alzheimer s Research & Therapy, Journal Year: 2020, Volume and Issue: 12(1)

Published: Dec. 1, 2020

COVID-19 is primarily a respiratory disease but up to two thirds of hospitalised patients show evidence central nervous system (CNS) damage, predominantly ischaemic, in some cases haemorrhagic and occasionally encephalitic. It unclear how much the ischaemic damage mediated by direct or inflammatory effects virus on CNS vasculature secondary extracranial cardiorespiratory disease. Limited data suggest that causative SARS-CoV-2 may enter via nasal mucosa olfactory fibres, haematogenous spread, capable infecting endothelial cells, pericytes probably neurons. Extracranially, targets cells pericytes, causing cell dysfunction, vascular leakage immune activation, sometimes leading disseminated intravascular coagulation. remains be confirmed whether cerebral are similarly targeted. Several aspects likely impact cognition. Cerebral white matter particularly vulnerable also critically important for cognitive function. There accumulating hypoperfusion accelerates amyloid-β (Aβ) accumulation linked tau TDP-43 pathology, inducing phosphorylation α-synuclein at serine-129, ischaemia increase risk development Lewy body Current therapies understandably focused supporting function, preventing thrombosis reducing activation. Since angiotensin-converting enzyme (ACE)-2 receptor SARS-CoV-2, ACE inhibitors angiotensin blockers predicted ACE-2 expression, it was initially feared their use might exacerbate COVID-19. Recent meta-analyses have instead suggested these medications protective. This perhaps because entry deplete ACE-2, tipping balance towards II-ACE-1-mediated classical RAS activation: exacerbating promoting inflammation. relevant APOE ε4 individuals, who seem increased COVID-19, lowest activity. leave an unexpected legacy long-term neurological complications significant number survivors. Cognitive follow-up will important, especially develop cerebrovascular during acute illness.

Language: Английский

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Implications of Phosphoinositide 3-Kinase-Akt (PI3K-Akt) Pathway in the Pathogenesis of Alzheimer’s Disease

Molecular Neurobiology, Journal Year: 2021, Volume and Issue: 59(1), P. 354 - 385

Published: Oct. 26, 2021

Language: Английский

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The GLP-1 Agonist Semaglutide Ameliorates Cognitive Regression in P301S Tauopathy Mice Model via Autophagy/ACE2/SIRT1/FOXO1-Mediated Microglia Polarization

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 177305 - 177305

Published: Jan. 1, 2025

Language: Английский

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Targeting amyloid clearance in Alzheimer's disease as a therapeutic strategy

British Journal of Pharmacology, Journal Year: 2019, Volume and Issue: 176(18), P. 3447 - 3463

Published: Feb. 2, 2019

Targeting the amyloid-β (Aβ) peptide cascade has been at heart of therapeutic developments in Alzheimer's disease (AD) research for more than 25 years, yet no successful drugs have reached marketplace based on this hypothesis. Nevertheless, genetic and other evidence remains strong, if not overwhelming, that Aβ is central to process. Most attention focused biosynthesis from its precursor protein through successive actions β- γ-secretases leading development inhibitors these membrane proteases. However, levels are maintained a balance clearance, which occurs both further proteolysis by family amyloid-degrading enzymes (ADEs) variety transport processes. The late-onset AD appears arise failure clearance mechanisms rather overproduction peptide. This review focuses nature mechanisms, particularly various proteases known be involved, their regulation potential as targets drug development. majority ADEs zinc metalloproteases [e.g., neprilysin (NEP) family, insulin-degrading enzyme, angiotensin converting (ACE)]. Strategies up-regulating expression activity enzymes, such genetic, epigenetic, stem cell technology, pharmacological approaches, will highlighted. Modifiable physiological affecting efficiency including brain perfusion, obesity, diabetes, sleep, also outlined. These new insights provide optimism future research. LINKED ARTICLES: article part themed section Therapeutics Dementia Disease: New Directions Precision Medicine. To view articles visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

Language: Английский

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ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2020, Volume and Issue: 139(3), P. 485 - 502

Published: Jan. 25, 2020

Mid-life hypertension and cerebrovascular dysfunction are associated with increased risk of later life dementia, including Alzheimer's disease (AD). The classical renin-angiotensin system (cRAS), a physiological regulator blood pressure, functions independently within the brain is overactive in AD. cRAS-targeting anti-hypertensive drugs reduced incidence AD, delayed onset cognitive decline, levels Aβ tau both animal models human pathological studies. cRAS activity moderated by downstream regulatory RAS pathway (rRAS), which underactive AD strongly hallmarks decline CNS disease. We now show that enhancement ACE2 activity, major effector rRAS, intraperitoneal administration diminazene aceturate (DIZE), an established activator ACE2, lowered hippocampal restored cognition mid-aged (13-14-month-old) symptomatic Tg2576 mice. confirmed protective effects DIZE were directly mediated through soluble Aβ42 IL1-β levels. MasR conjunction NMDA NR2B ERK signalling expression synaptosomes from Chronic (10 weeks) to pre-symptomatic 9-10-month-old mice, acute days) treatment cognitively impaired 12-13-month-old prevented development impairment. Together these data demonstrate protects against reverses amyloid-related pathology impairment preclinical model

Language: Английский

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Targeting brain Renin-Angiotensin System for the prevention and treatment of Alzheimer’s disease: Past, present and future

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 77, P. 101612 - 101612

Published: March 26, 2022

Alzheimer's disease (AD) is a well-known neurodegenerative characterized by the presence of two main hallmarks – Tau hyperphosphorylation and Aβ deposits. Notwithstanding, in last few years scientific evidence about drivers AD have been changing nowadays age-related vascular alterations several cardiovascular risk factors shown to trigger development AD. In this context, drugs targeting Renin Angiotensin System (RAS), commonly used for treatment hypertension, are evidencing high potential delay due their action on brain RAS. Indeed, ACE 1/Ang II/AT1R axis believed be upregulated responsible deleterious effects such as increased oxidative stress, neuroinflammation, blood-brain barrier (BBB) hyperpermeability, astrocytes dysfunction decrease cerebral blood flow. contrast, alternative II/AT2R; 2/Ang (1−7)/MasR; Ang IV/ AT4R(IRAP) seems counterbalance principal exert beneficial memory cognition. Accordingly, retrospective studies demonstrate reduced developing among people taking RAS medication well vitro vivo pre-clinical it herein critically reviewed. review, we first revise, at glance, pathophysiology focused its classic hallmarks. Secondly, an overview impact also provided, four essential axes II/AT1R. Finally, therapeutic available AD, namely angiotensin II receptor blockers (ARBs) converting enzyme inhibitors (ACEIs), highlighted data supporting hope will presented, from clinical studies.

Language: Английский

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The COVID-19 pandemic and Alzheimer’s disease: mutual risks and mechanisms

Translational Neurodegeneration, Journal Year: 2022, Volume and Issue: 11(1)

Published: Sept. 11, 2022

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a life-threatening disease, especially in elderly individuals and those with comorbidities. The predominant clinical manifestation of COVID-19 dysfunction, while neurological presentations are increasingly being recognized. SARS-CoV-2 invades host cells primarily via attachment the spike protein to angiotensin-converting enzyme (ACE2) receptor expressed on cell membranes. Patients Alzheimer's (AD) more susceptible infection prone outcomes. Recent studies have revealed some common risk factors for AD COVID-19. An understanding association between potential related mechanisms may lead development novel approaches treating both diseases. In present review, we first summarize central nervous system (CNS) then discuss associations shared key AD, focus ACE2 receptor, apolipoprotein E (APOE) genotype, age, neuroinflammation.

Language: Английский

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Dapagliflozin as an autophagic enhancer via LKB1/AMPK/SIRT1 pathway in ovariectomized/d-galactose Alzheimer’s rat model

Inflammopharmacology, Journal Year: 2022, Volume and Issue: 30(6), P. 2505 - 2520

Published: April 1, 2022

Abstract Autophagy and mitochondrial deficits are characteristics of early phase Alzheimer’s disease (AD). Sodium-glucose cotransporter-2 inhibitors have been nominated as a promising class against AD hallmarks. However, there no available data yet to discuss the impact gliflozins on autophagic pathways in AD. Peripherally, dapagliflozin’s (DAPA) effect is mostly owed signals. Thus, goal this study screen power DAPA centrally LKB1/AMPK/SIRT1/mTOR signaling ovariectomized/ d -galactose (OVX/ -Gal) rat model. Animals were arbitrarily distributed between 5 groups; first group undergone sham operation, while remaining groups OVX followed by -Gal (150 mg/kg/day; i.p.) for 70 days. After 6 weeks, third, fourth, fifth received (1 p.o.); concomitantly with AMPK inhibitor dorsomorphin (DORSO, 25 µg/rat, i.v.) fourth SIRT1 EX-527 (10 group. mitigated cognitive OVX/ rats, mirrored neurobehavioral task hippocampal histopathological examination immunohistochemical aggregates p-Tau. The neuroprotective was manifested elevation energy sensors; AMP/ATP ratio LKB1/AMPK protein expressions along markers; SIRT1, Beclin1, LC3B expressions. Downstream latter, boosted mTOR function; TFAM, contrary lessened BACE1. Herein, DORSO or co-administration prohibited DAPA’s actions where elucidated direct LKB1 its indirect SIRT1. Therefore, implied anti-AD effect, at least part, via boosting Graphical abstract

Language: Английский

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Links between COVID-19 and Alzheimer’s Disease—What Do We Already Know?

International Journal of Environmental Research and Public Health, Journal Year: 2023, Volume and Issue: 20(3), P. 2146 - 2146

Published: Jan. 25, 2023

Alzheimer’s disease (AD) is a life-changing condition whose etiology explained by several hypotheses. Recently, new virus contributed to the evidence of viral involvement in AD: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19 disease. AD was found be one most common comorbidities, and it increase mortality from this as well. Moreover, patients were observed present with distinct clinical features COVID-19, delirium being prevalent group. The SARS-CoV-2 enters host cells through angiotensin-converting enzyme (ACE2) receptor. ACE2 overexpressed brains AD, thus increases invasion. Furthermore, inhibition receptor may also decrease brain-derived neurotrophic factor (BDNF), contributing neurodegeneration. ApoE ε4 allele, risk facilitate entry into cells. neuroinflammation oxidative stress existing enhance inflammatory response associated COVID-19. pandemic social distancing measures negatively affected mental health, cognitive function, neuro-psychiatric symptoms patients. This review comprehensively covers links between disease, including presentation, molecular mechanisms, effects distancing.

Language: Английский

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Neuroprotective potential of Erigeron bonariensis ethanolic extract against ovariectomized/D-galactose-induced memory impairments in female rats in relation to its metabolite fingerprint as revealed using UPLC/MS

Inflammopharmacology, Journal Year: 2024, Volume and Issue: 32(2), P. 1091 - 1112

Published: Jan. 31, 2024

Abstract Erigeron bonariensis is widely distributed throughout the world's tropics and subtropics. In folk medicine, E. has historically been used to treat head brain diseases. Alzheimer’s disease (AD) most widespread form of dementia initiated via disturbances in function. Herein, neuroprotective effect chemically characterized ethanolic extract reported for first time an AD animal model. Chemical profiling was conducted using UPLC–ESI-MS analysis. Female rats underwent ovariectomy (OVX) followed by 42 days D-galactose (D-Gal) administration (150 mg/kg/day, i.p) induce AD. The OVX/D-Gal-subjected received either donepezil (5 mg/kg/day) or at 50, 100, 200 given 1 h prior D-Gal. analysis identified chemicals, including flavonoids, phenolic acids, terpenes, nitrogenous constituents. Several metabolites, such as isoschaftoside, casticin, velutin, pantothenic acid, xanthurenic C18-sphingosine, linoleamide, erucamide, were herein genus. Treatment with mitigated cognitive decline Morris Water Maze test histopathological alterations cortical hippocampal tissues rats. Moreover, OVX/D-Gal-induced Aβ aggregation, Tau hyperphosphorylation, AChE activity, neuroinflammation (NF-κBp65, TNF-α, IL-1β), apoptosis (Cytc, BAX). Additionally, ameliorated increasing α7-nAChRs expression, down-regulating GSK-3β FOXO3a modulating Jak2/STAT3/NF-ĸB p65 PI3K/AKT signaling cascades. These findings demonstrate memory-enhancing effects OVX/D-Gal rat model, highlighting its potential a promising candidate management. Graphical

Language: Английский

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