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1.
Folia Neuropathol ; 59(3): 232-238, 2021.
Article in English | MEDLINE | ID: covidwho-1463957

ABSTRACT

The major route of entry for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) into human host cells is by means of the angiotensin-converting enzyme-2 (ACE2) transmembrane receptor. This zinc-containing carboxypeptidase and membrane-integral surface receptor is ubiquitous and widely expressed in multiple cell types. Hence SARS-CoV-2, an unusually large RNA virus that causes coronavirus disease 2019 (COVID-19) has the remarkable capacity to invade many different types of human host cells simultaneously. Although COVID-19 is generally considered to be primarily an acute respiratory disease SARS-CoV-2 also targets specific anatomical regions of the central nervous system (CNS). In the normal CNS the highest ACE2 levels of expression are found within the medullary respiratory centers of the brainstem and this, in part, may explain the susceptibility of numerous COVID-19 patients to severe respiratory distress. About ~35% of all COVID-19 patients experience neurological and neuropsychiatric symptoms, and a pre-existing diagnosis of Alzheimer's disease (AD) predicts the highest risk of COVID-19 yet identified, with the highest mortality among elderly AD patients. In the current study of multiple anatomical regions of AD brains compared to age-, post-mortem interval- and gender-matched controls (n = 10 regions, n = 32 brains), ACE2 expression was found to be significantly up-regulated in AD in the occipital lobe, temporal lobe neocortex and hippocampal CA1. The temporal lobe and hippocampus of the brain are also targeted by the inflammatory neuropathology that accompanies AD, suggesting a significant mechanistic overlap between COVID-19 and AD, strongly centered on invasion by the neurotropic SARS-CoV-2 virus via the increased presence of ACE2 receptors in limbic regions of the AD-affected brain.


Subject(s)
Alzheimer Disease/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Brain/metabolism , COVID-19 , Aged , Aged, 80 and over , Female , Humans , Male , SARS-CoV-2 , Up-Regulation
2.
Int J Mol Sci ; 22(15)2021 Jul 30.
Article in English | MEDLINE | ID: covidwho-1350316

ABSTRACT

Increasing evidence suggests that elderly people with dementia are vulnerable to the development of severe coronavirus disease 2019 (COVID-19). In Alzheimer's disease (AD), the major form of dementia, ß-amyloid (Aß) levels in the blood are increased; however, the impact of elevated Aß levels on the progression of COVID-19 remains largely unknown. Here, our findings demonstrate that Aß1-42, but not Aß1-40, bound to various viral proteins with a preferentially high affinity for the spike protein S1 subunit (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the viral receptor, angiotensin-converting enzyme 2 (ACE2). These bindings were mainly through the C-terminal residues of Aß1-42. Furthermore, Aß1-42 strengthened the binding of the S1 of SARS-CoV-2 to ACE2 and increased the viral entry and production of IL-6 in a SARS-CoV-2 pseudovirus infection model. Intriguingly, data from a surrogate mouse model with intravenous inoculation of Aß1-42 show that the clearance of Aß1-42 in the blood was dampened in the presence of the extracellular domain of the spike protein trimers of SARS-CoV-2, whose effects can be prevented by a novel anti-Aß antibody. In conclusion, these findings suggest that the binding of Aß1-42 to the S1 of SARS-CoV-2 and ACE2 may have a negative impact on the course and severity of SARS-CoV-2 infection. Further investigations are warranted to elucidate the underlying mechanisms and examine whether reducing the level of Aß1-42 in the blood is beneficial to the fight against COVID-19 and AD.


Subject(s)
Amyloid beta-Peptides/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Peptide Fragments/metabolism , SARS-CoV-2/enzymology , Spike Glycoprotein, Coronavirus/metabolism , A549 Cells , Alzheimer Disease/complications , Alzheimer Disease/metabolism , Amyloid beta-Peptides/chemistry , Animals , COVID-19/complications , COVID-19/metabolism , Chlorocebus aethiops , Humans , Interleukin-6/metabolism , Mice, Inbred C57BL , Mice, Transgenic , Peptide Fragments/chemistry , Protein Subunits/chemistry , Protein Subunits/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells , Virus Internalization
3.
Mol Neurobiol ; 58(10): 5356-5368, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1326854

ABSTRACT

The pandemic of novel coronavirus 2 (SARS-CoV-2) has made global chaos for normal human living. Despite common COVID-19 symptoms, variability in clinical phenotypes was reported worldwide. Reports on SARS-CoV-2 suggest causing neurological manifestation. In addition, the susceptibility of SARS-CoV-2 in patients with neurodegenerative diseases and its complexity are largely unclear. Here, we aimed to demonstrate the possible transport of exosome from SARS-CoV-2-infected lungs to the brain regions associated with neurodegenerative diseases using multiple transcriptome datasets of SARS-CoV-2-infected lungs, RNA profiles from lung exosome, and gene expression profiles of the human brain. Upon transport, the transcription factors localized in the exosome regulate genes at lateral substantia nigra, medial substantia nigra, and superior frontal gyrus regions of Parkinson's disease (PD) and frontal cortex, hippocampus, and temporal cortex of Alzheimer's disease (AD). On SARS-CoV-2 infection, BCL3, JUND, MXD1, IRF2, IRF9, and STAT1 transcription factors in the exosomes influence the neuronal gene regulatory network and accelerate neurodegeneration. STAT1 transcription factor regulates 64 PD genes at lateral substantia nigra, 65 at superior frontal gyrus, and 19 at medial substantia nigra. Similarly, in AD, STAT1 regulates 74 AD genes at the temporal cortex, 40 genes at the hippocampus, and 16 genes at the frontal cortex. We further demonstrate that dysregulated neuronal genes showed involvement in immune response, signal transduction, apoptosis, and stress response process. In conclusion, SARS-CoV-2 may dysregulate neuronal gene regulatory network through exosomes that attenuate disease severity of neurodegeneration.


Subject(s)
Brain/metabolism , COVID-19/metabolism , Exosomes/metabolism , Lung/metabolism , Neurons/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Databases, Factual , Exosomes/genetics , Humans , Parkinson Disease/genetics , Parkinson Disease/metabolism , Transcriptome
4.
Med Sci Monit ; 27: e934077, 2021 Jul 26.
Article in English | MEDLINE | ID: covidwho-1326004

ABSTRACT

Current treatments for patients with Alzheimer's disease aim to improve behavioral, cognitive, and non-cognitive symptoms. There have been no new drug approvals for preventing or treating Alzheimer's disease for more than two decades. Drug development in Alzheimer's disease aims to identify disease-modifying therapies that will delay or slow the clinical course of this disease. More than 50% of the current Alzheimer's disease drug pipeline now involves immunotherapies or oral small molecule agents. The most promising disease-modifying drug targets are amyloid ß and tau protein. In June 2021, aducanumab, a humanized recombinant monoclonal antibody to amyloid ß, was the first potential disease-modifying therapy approved by the US Food and Drug Administration (FDA) to treat Alzheimer's disease and mild cognitive impairment. Accelerated approval of aducanumab was based on the results of only one of two phase 3 clinical trials. Several clinical trials of targeted disease-modifying immunotherapies to the tau protein and amyloid ß that commenced before the current COVID-19 pandemic have been delayed. This Editorial aims to provide an update on past, present, and future disease-modifying therapies in Alzheimer's disease, including targeted therapies for amyloid ß and tau protein.


Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , tau Proteins/metabolism , Antibodies, Monoclonal, Humanized/therapeutic use , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/immunology , Humans , Immunotherapy/methods , Immunotherapy/trends , Tauopathies/drug therapy
5.
Int J Mol Sci ; 22(13)2021 Jun 29.
Article in English | MEDLINE | ID: covidwho-1304667

ABSTRACT

Amyloid beta (Aß)-induced abnormal neuroinflammation is recognized as a major pathological feature of Alzheimer's disease (AD), which results in memory impairment. Research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease, or it is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, are crucial components of the innate immune system and are usually activated in response to infection or tissue damage. Although inflammasome activation plays critical roles against various pathogens in host defense, overactivation of inflammasome contributes to the pathogenesis of inflammatory diseases, including acute central nervous system (CNS) injuries and chronic neurodegenerative diseases, such as AD. This review summarizes the current literature on the role of the NLRP3 inflammasome in the pathogenesis of AD, and its involvement in infections, particularly SARS-CoV-2. NLRP3 might represent the crossroad between the hypothesized neurodegeneration and the primary COVID-19 infection.


Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Alzheimer Disease/metabolism , Animals , Coronavirus/pathogenicity , Humans , Immunity, Innate , Microglia/metabolism , Virus Diseases/immunology , Virus Diseases/pathology
6.
Aging (Albany NY) ; 13(11): 14552-14556, 2021 Jun 11.
Article in English | MEDLINE | ID: covidwho-1267005

ABSTRACT

SARS-CoV-2 more readily affects the elderly, especially as they present co-morbidities. In the COVID-19 pathogeny, ACE2 appears to be the key cell receptor for SARS-CoV-2 to infect humans. The level of ACE2 gene expression influences the susceptibility of contracting SARS-CoV-2. In circumstances in which the ACE2 level is low, the incidence of Covid-19 seems to be fewer. Two clinical patterns illustrate this observation, i. e., in infants and in Alzheimer's disease (AD). Very young children and AD patients get little COVID-19, in part probably due to decreased expression of ACE2. The determination of the nasal level of ACE2 gene expression could provide a useful scale to predict the susceptibility to contract the SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/etiology , SARS-CoV-2/metabolism , Alzheimer Disease/complications , Alzheimer Disease/metabolism , COVID-19/metabolism , Cerebrum/metabolism , Disease Susceptibility , Gene Expression , Humans , Infant , Nasal Mucosa/metabolism
7.
Adv Food Nutr Res ; 96: 251-310, 2021.
Article in English | MEDLINE | ID: covidwho-1240122

ABSTRACT

Since the discovery of manifest Zn deficiency in 1961, the increasing number of studies demonstrated the association between altered Zn status and multiple diseases. In this chapter, we provide a review of the most recent advances on the role of Zn in health and disease (2010-20), with a special focus on the role of Zn in neurodegenerative and neurodevelopmental disorders, diabetes and obesity, male and female reproduction, as well as COVID-19. In parallel with the revealed tight association between ASD risk and severity and Zn status, the particular mechanisms linking Zn2+ and ASD pathogenesis like modulation of synaptic plasticity through ProSAP/Shank scaffold, neurotransmitter metabolism, and gut microbiota, have been elucidated. The increasing body of data indicate the potential involvement of Zn2+ metabolism in neurodegeneration. Systemic Zn levels in Alzheimer's and Parkinson's disease were found to be reduced, whereas its sequestration in brain may result in modulation of amyloid ß and α-synuclein processing with subsequent toxic effects. Zn2+ was shown to possess adipotropic effects through the role of zinc transporters, zinc finger proteins, and Zn-α2-glycoprotein in adipose tissue physiology, underlying its particular role in pathogenesis of obesity and diabetes mellitus type 2. Recent findings also contribute to further understanding of the role of Zn2+ in spermatogenesis and sperm functioning, as well as oocyte development and fertilization. Finally, Zn2+ was shown to be the potential adjuvant therapy in management of novel coronavirus infection (COVID-19), underlining the perspectives of zinc in management of old and new threats.


Subject(s)
Autism Spectrum Disorder/metabolism , COVID-19/metabolism , Diabetes Mellitus, Type 2/metabolism , Neurodegenerative Diseases/metabolism , Obesity/metabolism , Reproduction , Zinc/metabolism , Alzheimer Disease/metabolism , Animals , COVID-19/drug therapy , Female , Humans , Male , Neurodevelopmental Disorders/metabolism , Nutritional Status , Parkinson Disease/metabolism , Zinc/deficiency , Zinc/therapeutic use
8.
Int J Mol Sci ; 22(4)2021 Feb 08.
Article in English | MEDLINE | ID: covidwho-1069829

ABSTRACT

Alzheimer's disease is a chronic neurodegenerative disorder and represents the main cause of dementia globally. Currently, the world is suffering from the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a virus that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of patients with Alzheimer's disease. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer's disease and ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease, and brains with the disease examined in this study also exhibited higher carbonylated proteins, as well as an increased thiol oxidation state of peroxiredoxin 6 (Prx6). A moderate positive correlation was found between the increased ACE2 protein expression and oxidative stress in brains with Alzheimer's disease. In summary, the present study reveals the relationships between Alzheimer's disease and ACE2, the receptor for SARS-CoV-2. These results suggest the importance of carefully monitoring patients with both Alzheimer's disease and COVID-19 in order to identify higher viral loads in the brain and long-term adverse neurological consequences.


Subject(s)
Alzheimer Disease/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/epidemiology , COVID-19/metabolism , Hippocampus/metabolism , Pandemics , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Up-Regulation , Alzheimer Disease/complications , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Autopsy , COVID-19/complications , COVID-19/virology , Hippocampus/pathology , Humans , Oxidation-Reduction , Oxidative Stress , Peroxiredoxin VI/metabolism , Plaque, Amyloid/metabolism , Protein Carbonylation , Severity of Illness Index , Virus Internalization
9.
Biomolecules ; 10(8)2020 08 07.
Article in English | MEDLINE | ID: covidwho-823584

ABSTRACT

Neurodegenerative diseases are the second most common cause of death and characterized by progressive impairments in movement or mental functioning in the central or peripheral nervous system. The prevention of neurodegenerative disorders has become an emerging public health challenge for our society. Melatonin, a pineal hormone, has various physiological functions in the brain, including regulating circadian rhythms, clearing free radicals, inhibiting biomolecular oxidation, and suppressing neuroinflammation. Cumulative evidence indicates that melatonin has a wide range of neuroprotective roles by regulating pathophysiological mechanisms and signaling pathways. Moreover, melatonin levels are decreased in patients with neurodegenerative diseases. In this review, we summarize current knowledge on the regulation, molecular mechanisms and biological functions of melatonin in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, vascular dementia and multiple sclerosis. We also discuss the clinical application of melatonin in neurodegenerative disorders. This information will lead to a better understanding of the regulation of melatonin in the brain and provide therapeutic options for the treatment of various neurodegenerative diseases.


Subject(s)
Circadian Rhythm , Melatonin/physiology , Neurodegenerative Diseases/metabolism , Oxidative Stress , Alzheimer Disease/metabolism , Amyotrophic Lateral Sclerosis/metabolism , Animals , Circadian Rhythm/drug effects , Dementia, Vascular/metabolism , Humans , Huntington Disease/metabolism , Melatonin/therapeutic use , Multiple Sclerosis/metabolism , Neurodegenerative Diseases/drug therapy , Oxidative Stress/drug effects , Parkinson Disease/metabolism
10.
ACS Chem Neurosci ; 11(15): 2145-2148, 2020 08 05.
Article in English | MEDLINE | ID: covidwho-646274

ABSTRACT

Studies have shown that the calcium ion (Ca2+) plays important roles both in Alzheimer's dementia and SARS-CoV S-mediated fusion to host cell entry. An elevated level of intracellular calcium causes neuronal dysfunction, cell death, and apoptosis. Dysregulation of calcium has also been shown to increase the production of amyloid beta (Aß) protein, the hallmark of Alzheimer's dementia. Reversely, deposition of Aß is also responsible for calcium dysregulation. On the other hand, it has been well investigated that viruses can disturb host cell Ca2+ homeostasis as well as modulate signal transduction mechanisms. Viruses can also hijack the host cell calcium channels and pumps to release more intracellular Ca2+ to utilize for their life cycle. Even though evidence has not been reported on SARS-CoV-2 concerning Ca2+ regulation, however, it has been well established that Ca2+ is essential for viral entry, viral gene replication, and virion maturation and release. Recent reports suggest that SARS-CoV needs two Ca2+ ions to fuse with the host cell at the entry step. Furthermore, some calcium channel blockers (CCBs), such as nimodipine, memantine, etc., have been reported to be effective in the treatment of dementia in Alzheimer's disease (AD) as well as have shown inhibition in various virus infections.


Subject(s)
Alzheimer Disease/drug therapy , Betacoronavirus , Calcium Channel Blockers/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/psychology , COVID-19 , Calcium/metabolism , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/pharmacology , Calcium Channels/metabolism , Coronavirus Infections/metabolism , Coronavirus Infections/psychology , Humans , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/psychology , SARS-CoV-2 , Treatment Outcome
11.
J Alzheimers Dis ; 76(1): 27-31, 2020.
Article in English | MEDLINE | ID: covidwho-637281

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic led to an abrupt halt of many Alzheimer's disease (AD) research studies at sites spanning the world. This is especially true for studies requiring in-person contact, such as studies collecting biofluids. Since COVID-19 is likely to remain a threat for an extended period, the resumption of fluid biomarker studies requires the development and implementation of procedures that minimize the risk of in-person visits to participants, staff, and individuals handling the biofluid samples. Some issues to consider include structuring the visit workflow to minimize contacts and promote social distancing; screening and/or testing participants and staff for COVID-19; wearing masks and performing hand hygiene; and precautions for handling, storing, and analyzing biofluids. AD fluid biomarker research remains a vitally important public health priority and resuming studies requires appropriate safety procedures to protect research participants and staff.


Subject(s)
Alzheimer Disease/metabolism , Betacoronavirus , Coronavirus Infections/metabolism , Health Personnel/trends , Patient Safety , Personal Protective Equipment , Pneumonia, Viral/metabolism , Alzheimer Disease/diagnosis , Biomarkers/metabolism , Body Fluids/metabolism , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/transmission , Humans , Pandemics , Personal Protective Equipment/trends , Pneumonia, Viral/diagnosis , Pneumonia, Viral/transmission , SARS-CoV-2
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