Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer’s disease pathology in mouse models of Alzheimer’s disease

MacLachlan, Robert A.; Evans, Charles E.; Chai, Siew Yeen; Good, Mark Andrew; Kehoe, Patrick Gavin; Miners, Scott

doi:10.1016/j.nbas.2022.100062

Cited by 2 publications

(2 citation statements)

References 55 publications

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“…The RADAR Trial, a double-blind, randomized, placebo-controlled, phase 2 trial concluded that 12 months' treatment with losartan (an AT1R Ang II receptor blocker) was not effective in reducing the rate of brain atrophy in Alzheimer's patients [65]. In mouse models of Alzheimer's disease, the reduction in ACE2 levels and activity and increased Ang II did not exacerbate Alzheimer's disease pathology [66]. Furthermore, while it is widely thought that AT1R mediates the pathogenesis of Alzheimer's disease [67], Ang II can activate AT1R and AT2R, which could exert opposite biological effects.…”

Section: Alternative To the Stated Hypothesismentioning

confidence: 99%

The Role of Furin in the Pathogenesis of COVID-19-Associated Neurological Disorders

Ayyubova,

Gychka,

Nikolaienko

et al. 2024

Life

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Neurological disorders have been reported in a large number of coronavirus disease 2019 (COVID-19) patients, suggesting that this disease may have long-term adverse neurological consequences. COVID-19 occurs from infection by a positive-sense single-stranded RNA virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The membrane fusion protein of SARS-CoV-2, the spike protein, binds to its human host receptor, angiotensin-converting enzyme 2 (ACE2), to initiate membrane fusion between the virus and host cell. The spike protein of SARS-CoV-2 contains the furin protease recognition site and its cleavage enhances the infectivity of this virus. The binding of SARS-CoV-2 to the ACE2 receptor has been shown to downregulate ACE2, thereby increasing the levels of pathogenic angiotensin II (Ang II). The furin protease cleaves between the S1 subunit of the spike protein with the binding domain toward ACE2 and the S2 subunit with the transmembrane domain that anchors to the viral membrane, and this activity releases the S1 subunit into the blood circulation. The released S1 subunit of the spike protein also binds to and downregulates ACE2, in turn increasing the level of Ang II. Considering that a viral particle contains many spike protein molecules, furin-dependent cleavage would release many free S1 protein molecules, each of which can downregulate ACE2, while infection with a viral particle only affects one ACE2 molecule. Therefore, the furin-dependent release of S1 protein would dramatically amplify the ability to downregulate ACE2 and produce Ang II. We hypothesize that this amplification mechanism that the virus possesses, but not the infection per se, is the major driving force behind COVID-19-associated neurological disorders.

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Section: Alternative To the Stated Hypothesismentioning

confidence: 99%

The Role of Furin in the Pathogenesis of COVID-19-Associated Neurological Disorders

Ayyubova,

Gychka,

Nikolaienko

et al. 2024

Life

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“…Renin-angiotensin system (RAS) has two major axes. The classical axis ACE/Ang II/angiotensin II type 1 receptor (AT1R), and the counter-regulatory axes ACE-2/Angiotensin 1–7 (Ang 1–7) Mas receptor (MasR) and ACE2/Ang 1–9/AT2R ( Sepulveda-Fragoso et al, 2021 ; MacLachlan et al, 2023 ). The Mas axis was identified recently as a factor involved in macrophage function during inflammatory processes in vascular and central nervous systems ( Hammer et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Role of monocytes/macrophages in renin-angiotensin system-induced hypertension and end organ damage

Barhoumi,

Todryk

2023

Front. Physiol.

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Graphical AbstractRole of monocytes/macrophages in renin-angiotensin system-induced hypertension and end organ damage. RAS activation induces monocyte/macrophage pro-inflammatory-like phenotype polarization, directly and indirectly via cytokines (MCP-1, CCR2, IL-1b). Activation manifests in fibrosis, oxidative stress, endothelial dysfunction and low grade inflammation (IL-6, TNFa) and tus end organ damage. (HTA hypertension).

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Age-related reduction in brain ACE-2 is not exacerbated by Alzheimer’s disease pathology in mouse models of Alzheimer’s disease

Cited by 2 publications

References 55 publications

The Role of Furin in the Pathogenesis of COVID-19-Associated Neurological Disorders

The Role of Furin in the Pathogenesis of COVID-19-Associated Neurological Disorders

Role of monocytes/macrophages in renin-angiotensin system-induced hypertension and end organ damage

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