Higher Angiotensin I Converting Enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer’s disease

Reveret, Louise; Leclerc, Manon; Émond, Vincent; Loiselle, Andréanne; Bourassa, Philippe; Tremblay, Cyntia; Bennett, David A.; Hébert, Sébastien; Calon, Frédéric

doi:10.1101/2023.01.17.524254

Cited by 4 publications

(5 citation statements)

References 93 publications

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“…Patients who died of COVID-19 showed downregulated ACE2 protein expression at a very low level (Panel (b)). Consistent with previously reported Western blotting and RT-PCR results obtained by our laboratory as well as others [53][54][55][56], ACE2 expression levels were higher in the brains of Alzheimer's disease patients compared to controls as monitored by immunohistochemistry (Panel (c)). Even in Alzheimer's brains, COVID-19 decreased the protein expression of ACE2, but only to a level that was higher than in the brains of COVID-19 patients without Alzheimer's disease (Panel (d)).…”

Section: Evaluation Of the Hypothesissupporting

confidence: 92%

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: Evaluation Of the Hypothesissupporting

confidence: 92%

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

Ayyubova,

Gychka,

Nikolaienko

et al. 2024

Life

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show abstract

“…Patients who died of COVID-19 had downregulated ACE2 protein expression at a very low level (Panel b). Consistent with previously reported Western blotting and RT-PCR results obtained by our laboratory as well as others [53][54][55][56], ACE2 expression levels are higher in the brain of Alzheimer's disease patients compared to controls as monitored by immunohistochemistry (Panel c). Even in Alzheimer's brains, COVID-19 decreased the protein expression of ACE2, but only to a level that is higher than in the brains of COVID-19 patients without Alzheimer's disease (Panel d).…”

Section: Evaluation Of the Hypothesissupporting

confidence: 92%

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

Ayyubova,

Gychka,

Nikolaienko

et al. 2023

Preprint

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Neurological disorders have been reported to occur in a large number of coronavirus disease 2019 (COVID-19) patients, suggesting that this disease may also exert long-term adverse neurological consequences. COVID-19 occurs due to the 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 S1 subunit of the spike protein with the binding domain toward ACE2 and S2 subunit with 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 would also bind to and downregulate ACE2, in turn, increasing the level of Ang II. Considering that a viral particle contains a number of the spike protein molecules, furin-dependent cleavage would release a large number of free S1 proteins each of which can downregulate ACE2, while the 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 the neurological disorders.

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“…ACE2, the SARS-CoV-2 receptor required for cell entry, is considered the most important determinant in dictating the greater susceptibility of developing AD among COVID-19 patients [108,112]. Microarray, Western blotting, Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR) and immunostaining analyses have undoubtedly shown that the expression levels of ACE2 significantly increase in the brain tissues of human AD subjects when compared with healthy, not-demented controls and in close relationship with the severity of clinical dementia and different neuropathological parameters, including the density of dystrophic neurites, the Aβ plaques and NFT accumulation [113][114][115]. In addition, in a SARS-CoV-2 pseudovirus infection model, the fibrillogenic and highly-neurotoxic Aβ1-42 peptide-but not the shorter Aβ1-40 one-binds to both the S1 protein and ACE2 receptor [116], by facilitating the virus invasion and production of IL-6.…”

Section: Ace2 and Ageingmentioning

confidence: 99%

“…Interestingly, the SARS-CoV-2 infection seems to instigate and/or accelerate the AD phenotype by inhibiting ACE2 enzymatic activity, triggering a hyperinflammatory response and downregulating the secretion of BDNF, a potent neurotrophin endowed with crucial functions in supporting neurogenesis, cognition and the prevention of neurodegeneration upon binding to its cognate transmembrane TrkB receptor protein [117]. In concomitance with an elevation in the mRNA transcript of ACE2 facilitating the entry points of SARS-CoV-2 in the CNS, a high level of its TBS/Detergent-soluble inactive form has also been detected in the parietal cortex of two large cohorts of AD-fully diagnosed subjects when compared to controls, suggesting that a defective brain RAS signaling with a consequent decrease in its anti-inflammatory and neuroprotective properties is more likely to take place in humans with a low cognitive score [115].…”

Section: Ace2 and Ageingmentioning

confidence: 99%

COVID-19 and Alzheimer’s Disease Share Common Neurological and Ophthalmological Manifestations: A Bidirectional Risk in the Post-Pandemic Future

Amadoro,

Latina,

Stigliano

et al. 2023

Cells

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A growing body of evidence indicates that a neuropathological cross-talk takes place between the coronavirus disease 2019 (COVID-19) -the pandemic severe pneumonia that has had a tremendous impact on the global economy and health since three years after its outbreak in December 2019- and Alzheimer’s Disease (AD), the leading cause of dementia among human beings, reaching 139 million by the year 2050. Even though COVID-19 is a primary respiratory disease, its causative agent, the so-called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), is also endowed with high neuro-invasive potential (Neurocovid). The neurological complications of COVID-19, resulting from the direct viral entry into the Central Nervous System (CNS) and/or indirect systemic inflammation and dysregulated activation of immune response, encompass memory decline and anosmia which are typically associated with AD symptomatology. In addition, patients diagnosed with AD are more vulnerable to SARS-CoV-2 infection and are inclined to more severe clinical outcomes. In the present review, we better elucidate the intimate connection between COVID-19 and AD by summarizing the involved risk factors/targets and the underlying biological mechanisms shared by these two disorders with a particular focus on the Angiotensin-Converting Enzyme 2 (ACE2) receptor, APOlipoprotein E (APOE), aging, neuroinflammation and cellular pathways associated with the Amyloid Precursor Protein (APP)/Amyloid beta (Aβ) and tau neuropathologies. Finally, the involvement of ophthalmological manifestations, including vitreo-retinal abnormalities and visual deficits, in both COVID-19 and AD are also discussed. Understanding the common physiopathological aspects linking COVID-19 and AD will pave the way to novel management and diagnostic/therapeutic approaches to cope with them in the post-pandemic future.

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Higher Angiotensin I Converting Enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer’s disease

Cited by 4 publications

References 93 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

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

COVID-19 and Alzheimer’s Disease Share Common Neurological and Ophthalmological Manifestations: A Bidirectional Risk in the Post-Pandemic Future

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