Alzheimer’s Disease: An Update and Insights Into Pathophysiology

Alzheimer’s disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key protein...

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Published in	Frontiers in aging neuroscience Vol. 14; p. 742408
Main Authors	Abubakar, Murtala Bello, Sanusi, Kamaldeen Olalekan, Ugusman, Azizah, Mohamed, Wael, Kamal, Haziq, Ibrahim, Nurul Husna, Khoo, Ching Soong, Kumar, Jaya
Format	Journal Article
Language	English
Published	Switzerland Frontiers Research Foundation 30.03.2022 Frontiers Media S.A
Subjects	1-Phosphatidylinositol 3-kinase Aging Neuroscience AKT protein Alzheimer Alzheimer's disease Apolipoprotein E4 Astrocytes Atrophy Basal forebrain Biological activity Cell cycle Clinical trials Cognitive ability COVID-19 Dementia diagnose Fibroblast growth factor receptor 2 Fibroblast growth factor receptor 7 Forebrain Glial cells Growth factors JAK Janus kinase 2 Kinases Medical diagnosis Metabolic pathways Metabolomics miRNA Nerve growth factor Neurodegenerative diseases Neuronal-glial interactions Neurotransmitters NGF omic Oxidative stress Pathogenesis Proteins Risk factors Signal transduction Stat3 protein therapeutic Vitamin E β-Amyloid therapeutic JAK diagnose dementia NGF omic Alzheimer vascular
Online Access	Get full text
ISSN	1663-4365 1663-4365
DOI	10.3389/fnagi.2022.742408

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Abstract	Alzheimer’s disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signaling pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted toward metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important “omics” tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual’s metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in “omics”-based biomarkers in AD.
AbstractList	Alzheimer's disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signaling pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted toward metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important "omics" tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual's metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in "omics"-based biomarkers in AD.Alzheimer's disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signaling pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted toward metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important "omics" tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual's metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in "omics"-based biomarkers in AD. Alzheimer's disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signaling pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted toward metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important "omics" tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual's metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in "omics"-based biomarkers in AD. Alzheimer disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before disease symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signal pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted towards metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important "omics" tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual's metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in “omics”-based biomarkers in AD.
Author	Mohamed, Wael Kamal, Haziq Abubakar, Murtala Bello Ibrahim, Nurul Husna Khoo, Ching Soong Sanusi, Kamaldeen Olalekan Ugusman, Azizah Kumar, Jaya
AuthorAffiliation	3 Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre , Kuala Lumpur , Malaysia 4 Department of Basic Medical Science, Kulliyyah of Medicine, International Islamic University Malaysia , Kuantan , Malaysia 1 Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University , Sokoto , Nigeria 2 Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University , Sokoto , Nigeria 6 Neurology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre , Kuala Lumpur , Malaysia 5 Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University , Shebin El-Kom , Egypt
AuthorAffiliation_xml	– name: 4 Department of Basic Medical Science, Kulliyyah of Medicine, International Islamic University Malaysia , Kuantan , Malaysia – name: 2 Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University , Sokoto , Nigeria – name: 3 Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre , Kuala Lumpur , Malaysia – name: 5 Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University , Shebin El-Kom , Egypt – name: 6 Neurology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre , Kuala Lumpur , Malaysia – name: 1 Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University , Sokoto , Nigeria
Author_xml	– sequence: 1 givenname: Murtala Bello surname: Abubakar fullname: Abubakar, Murtala Bello – sequence: 2 givenname: Kamaldeen Olalekan surname: Sanusi fullname: Sanusi, Kamaldeen Olalekan – sequence: 3 givenname: Azizah surname: Ugusman fullname: Ugusman, Azizah – sequence: 4 givenname: Wael surname: Mohamed fullname: Mohamed, Wael – sequence: 5 givenname: Haziq surname: Kamal fullname: Kamal, Haziq – sequence: 6 givenname: Nurul Husna surname: Ibrahim fullname: Ibrahim, Nurul Husna – sequence: 7 givenname: Ching Soong surname: Khoo fullname: Khoo, Ching Soong – sequence: 8 givenname: Jaya surname: Kumar fullname: Kumar, Jaya
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/35431894$$D View this record in MEDLINE/PubMed
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Copyright	Copyright © 2022 Abubakar, Sanusi, Ugusman, Mohamed, Kamal, Ibrahim, Khoo and Kumar. 2022. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. Copyright © 2022 Abubakar, Sanusi, Ugusman, Mohamed, Kamal, Ibrahim, Khoo and Kumar. 2022 Abubakar, Sanusi, Ugusman, Mohamed, Kamal, Ibrahim, Khoo and Kumar
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Keywords	therapeutic JAK diagnose dementia NGF omic Alzheimer vascular
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23 Edited by: Maria Grazia Giovannini, University of Florence, Italy This article was submitted to Alzheimer’s Disease and Related Dementias, a section of the journal Frontiers in Aging Neuroscience Reviewed by: Vijay Karkal Hegde, Texas Tech University, United States; Timothy Michael Ellmore, City College of New York (CUNY), United States; Idris Long, University of Science Malaysia, Malaysia; Igor Nikolayevich Iezhitsa, International Medical University, Malaysia
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Snippet	Alzheimer’s disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease... Alzheimer's disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease... Alzheimer disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease...
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SubjectTerms	1-Phosphatidylinositol 3-kinase Aging Neuroscience AKT protein Alzheimer Alzheimer's disease Apolipoprotein E4 Astrocytes Atrophy Basal forebrain Biological activity Cell cycle Clinical trials Cognitive ability COVID-19 Dementia diagnose Fibroblast growth factor receptor 2 Fibroblast growth factor receptor 7 Forebrain Glial cells Growth factors JAK Janus kinase 2 Kinases Medical diagnosis Metabolic pathways Metabolomics miRNA Nerve growth factor Neurodegenerative diseases Neuronal-glial interactions Neurotransmitters NGF omic Oxidative stress Pathogenesis Proteins Risk factors Signal transduction Stat3 protein therapeutic Vitamin E β-Amyloid
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Title	Alzheimer’s Disease: An Update and Insights Into Pathophysiology
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