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Molecular Mechanism of Alzheimer's Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2018) | Viewed by 86563

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Special Issue Editor

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is an age-related neurological disease that affects tens of millions of people, in addition to their carers. Hallmark features of AD include plaques composed of amyloid beta, as well as neurofibrillary tangles of tau protein. However, despite more than a century of study, the cause of Alzheimer’s disease remains unresolved. The roles of amyloid beta and tau are being questioned and other causes of AD are now under consideration. The contributions of researchers, model organisms, and various hypotheses will be examined in this Special Issue.

Prof. Ian Macreadie
Guest Editor

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Keywords

  • Alzheimer’s disease
  • amyloid beta
  • brain cholesterol
  • brain microbes
  • neurofibrillary tangles
  • neurodegeneration
  • neuroinflammation
  • oxidative stress
  • proteostasis
  • tau
  • type 3 diabetes

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Published Papers (13 papers)

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Research

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13 pages, 1095 KiB  
Article
Differential Methylation in APOE (Chr19; Exon Four; from 44,909,188 to 44,909,373/hg38) and Increased Apolipoprotein E Plasma Levels in Subjects with Mild Cognitive Impairment
by Oscar Mancera-Páez, Kelly Estrada-Orozco, María Fernanda Mahecha, Francy Cruz, Kely Bonilla-Vargas, Nicolás Sandoval, Esneyder Guerrero, David Salcedo-Tacuma, Jesús D. Melgarejo, Edwin Vega, Jenny Ortega-Rojas, Gustavo C. Román, Rodrigo Pardo-Turriago and Humberto Arboleda
Int. J. Mol. Sci. 2019, 20(6), 1394; https://doi.org/10.3390/ijms20061394 - 20 Mar 2019
Cited by 15 | Viewed by 3910
Abstract
Background: Biomarkers are essential for identification of individuals at high risk of mild cognitive impairment (MCI) for potential prevention of dementia. We investigated DNA methylation in the APOE gene and apolipoprotein E (ApoE) plasma levels as MCI biomarkers in Colombian subjects with MCI [...] Read more.
Background: Biomarkers are essential for identification of individuals at high risk of mild cognitive impairment (MCI) for potential prevention of dementia. We investigated DNA methylation in the APOE gene and apolipoprotein E (ApoE) plasma levels as MCI biomarkers in Colombian subjects with MCI and controls. Methods: In total, 100 participants were included (71% women; average age, 70 years; range, 43–91 years). MCI was diagnosed by neuropsychological testing, medical and social history, activities of daily living, cognitive symptoms and neuroimaging. Using multivariate logistic regression models adjusted by age and gender, we examined the risk association of MCI with plasma ApoE and APOE methylation. Results: MCI was diagnosed in 41 subjects (average age, 66.5 ± 9.6 years) and compared with 59 controls. Elevated plasma ApoE and APOE methylation of CpGs 165, 190, and 198 were risk factors for MCI (p < 0.05). Higher CpG-227 methylation correlated with lower risk for MCI (p = 0.002). Only CpG-227 was significantly correlated with plasma ApoE levels (correlation coefficient = −0.665; p = 0.008). Conclusion: Differential APOE methylation and increased plasma ApoE levels were correlated with MCI. These epigenetic patterns require confirmation in larger samples but could potentially be used as biomarkers to identify early stages of MCI. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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14 pages, 1823 KiB  
Article
miRNA-34c Overexpression Causes Dendritic Loss and Memory Decline
by Yu-Chia Kao, I-Fang Wang and Kuen-Jer Tsai
Int. J. Mol. Sci. 2018, 19(8), 2323; https://doi.org/10.3390/ijms19082323 - 08 Aug 2018
Cited by 23 | Viewed by 3678
Abstract
Microribonucleic acids (miRNAs) play a pivotal role in numerous aspects of the nervous system and are increasingly recognized as key regulators in neurodegenerative diseases. This study hypothesized that miR-34c, a miRNA expressed in mammalian hippocampi whose expression level can alter the hippocampal dendritic [...] Read more.
Microribonucleic acids (miRNAs) play a pivotal role in numerous aspects of the nervous system and are increasingly recognized as key regulators in neurodegenerative diseases. This study hypothesized that miR-34c, a miRNA expressed in mammalian hippocampi whose expression level can alter the hippocampal dendritic spine density, could induce memory impairment akin to that of patients with Alzheimer’s disease (AD) in mice. In this study, we showed that miR-34c overexpression in hippocampal neurons negatively regulated dendritic length and spine density. Hippocampal neurons transfected with miR-34c had shorter dendrites on average and fewer filopodia and spines than those not transfected with miR-34c (control mice). Because dendrites and synapses are key sites for signal transduction and fundamental structures for memory formation and storage, disrupted dendrites can contribute to AD. Therefore, we supposed that miR-34c, through its effects on dendritic spine density, influences synaptic plasticity and plays a key role in AD pathogenesis. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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18 pages, 719 KiB  
Article
Inherited and Acquired Decrease in Complement Receptor 1 (CR1) Density on Red Blood Cells Associated with High Levels of Soluble CR1 in Alzheimer’s Disease
by Rachid Mahmoudi, Sarah Feldman, Aymric Kisserli, Valérie Duret, Thierry Tabary, Laurie-Anne Bertholon, Sarah Badr, Vignon Nonnonhou, Aude Cesar, Antoine Neuraz, Jean Luc Novella and Jacques Henri Max Cohen
Int. J. Mol. Sci. 2018, 19(8), 2175; https://doi.org/10.3390/ijms19082175 - 25 Jul 2018
Cited by 15 | Viewed by 6335
Abstract
The complement receptor 1 (CR1) gene was shown to be involved in Alzheimer’s disease (AD). We previously showed that AD is associated with low density of the long CR1 isoform, CR1*2 (S). Here, we correlated phenotype data (CR1 density per erythrocyte [...] Read more.
The complement receptor 1 (CR1) gene was shown to be involved in Alzheimer’s disease (AD). We previously showed that AD is associated with low density of the long CR1 isoform, CR1*2 (S). Here, we correlated phenotype data (CR1 density per erythrocyte (CR1/E), blood soluble CR1 (sCR1)) with genetic data (density/length polymorphisms) in AD patients and healthy controls. CR1/E was enumerated using flow cytometry, while sCR1 was quantified by ELISA. CR1 polymorphisms were assessed using restriction fragment length polymorphism (RFLP), pyrosequencing, and high-resolution melting PCR. In AD patients carrying the H allele (HindIII polymorphism) or the Q allele (Q981H polymorphism), CR1/E was significantly lower when compared with controls carrying the same alleles (p < 0.01), contrary to sCR1, which was significantly higher (p < 0.001). Using multivariate analysis, a reduction of 6.68 units in density was associated with an increase of 1% in methylation of CR1 (estimate −6.68; 95% confidence intervals (CIs) −12.37, −0.99; p = 0.02). Our data show that, in addition to inherited genetic factors, low density of CR1/E is also acquired. The involvement of CR1 in the pathogenesis of AD might be linked to insufficient clearance of amyloid deposits. These findings may open perspectives for new therapeutic strategies in AD. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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9 pages, 1114 KiB  
Article
Development of Convenient System for Detecting Yeast Cell Stress, Including That of Amyloid Beta
by Yen Nhi Luu and Ian Macreadie
Int. J. Mol. Sci. 2018, 19(7), 2136; https://doi.org/10.3390/ijms19072136 - 23 Jul 2018
Cited by 9 | Viewed by 3948
Abstract
(1) Background: As a model eukaryote, the study of stress responses in yeast can be employed for studying human health and disease, and the effects of various drugs that may impact health. “Reporting” of stress in yeast has frequently utilised enzymes like β-galactosidase [...] Read more.
(1) Background: As a model eukaryote, the study of stress responses in yeast can be employed for studying human health and disease, and the effects of various drugs that may impact health. “Reporting” of stress in yeast has frequently utilised enzymes like β-galactosidase that require laborious assays for quantitative results. The use of a stress reporter that can be measured quantitatively and with high sensitivity in living cells in a multi-well plate reader is a more desirable approach; (2) Methods: A multi-copy yeast-Escherichia coli shuttle plasmid containing the HSP42 promoter upstream of the mCherry reporter, along with the URA3 selectable marker was constructed and tested; (3) Results: Under certain stress conditions inducing the heat shock response, transformants containing the plasmid produced red fluorescence that could be readily quantitated in a microtitre plate reader. Stresses that produced red fluorescence included exposure to heat shock, copper ions, oligomeric amyloid beta (Aβ42) and fibrillar Aβ42; (4) Conclusions: Being able to conveniently and quantitatively monitor stresses in whole live populations of yeast offers great opportunities to screen compounds and conditions that cause stress, as well as conditions that alleviate stress. While freshly prepared oligomeric amyloid beta has previously been shown to exhibit high toxicity, fibrils have been generally considered to be non-toxic or of low toxicity. In this study, fibrillar amyloid beta has also been shown to induce stress. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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14 pages, 2278 KiB  
Article
Multiple Layers of CDK5R1 Regulation in Alzheimer’s Disease Implicate Long Non-Coding RNAs
by Marco Spreafico, Barbara Grillo, Francesco Rusconi, Elena Battaglioli and Marco Venturin
Int. J. Mol. Sci. 2018, 19(7), 2022; https://doi.org/10.3390/ijms19072022 - 11 Jul 2018
Cited by 62 | Viewed by 5130
Abstract
Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) gene encodes for p35, the main activator of Cyclin-dependent kinase 5 (CDK5). The active p35/CDK5 complex is involved in numerous aspects of brain development and function, and its deregulation is closely associated to Alzheimer’s [...] Read more.
Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) gene encodes for p35, the main activator of Cyclin-dependent kinase 5 (CDK5). The active p35/CDK5 complex is involved in numerous aspects of brain development and function, and its deregulation is closely associated to Alzheimer’s disease (AD) onset and progression. We recently showed that miR-15/107 family can negatively regulate CDK5R1 expression modifying mRNA stability. Interestingly, miRNAs belonging to miR-15/107 family are downregulated in AD brain while CDK5R1 is upregulated. Long non-coding RNAs (lncRNAs) are emerging as master regulators of gene expression, including miRNAs, and their dysregulation has been implicated in the pathogenesis of AD. Here, we evaluated the existence of an additional layer of CDK5R1 expression regulation provided by lncRNAs. In particular, we focused on three lncRNAs potentially regulating CDK5R1 expression levels, based on existing data: NEAT1, HOTAIR, and MALAT1. We demonstrated that NEAT1 and HOTAIR negatively regulate CDK5R1 mRNA levels, while MALAT1 has a positive effect. We also showed that all three lncRNAs positively control miR-15/107 family of miRNAs. Moreover, we evaluated the expression of NEAT1, HOTAIR, and MALAT1 in AD and control brain tissues. Interestingly, NEAT1 displayed increased expression levels in temporal cortex and hippocampus of AD patients. Interestingly, we observed a strong positive correlation between CDK5R1 and NEAT1 expression levels in brain tissues, suggesting a possible neuroprotective role of NEAT1 in AD to compensate for increased CDK5R1 levels. Overall, our work provides evidence of another level of CDK5R1 expression regulation mediated by lncRNAs and points to NEAT1 as a biomarker, as well as a potential pharmacological target for AD therapy. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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Review

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15 pages, 879 KiB  
Review
Sleep Disturbance as a Potential Modifiable Risk Factor for Alzheimer’s Disease
by Eiko N. Minakawa, Keiji Wada and Yoshitaka Nagai
Int. J. Mol. Sci. 2019, 20(4), 803; https://doi.org/10.3390/ijms20040803 - 13 Feb 2019
Cited by 65 | Viewed by 9647
Abstract
Sleep disturbance is a common symptom in patients with various neurodegenerative diseases, including Alzheimer’s disease (AD), and it can manifest in the early stages of the disease. Impaired sleep in patients with AD has been attributed to AD pathology that affects brain regions [...] Read more.
Sleep disturbance is a common symptom in patients with various neurodegenerative diseases, including Alzheimer’s disease (AD), and it can manifest in the early stages of the disease. Impaired sleep in patients with AD has been attributed to AD pathology that affects brain regions regulating the sleep–wake or circadian rhythm. However, recent epidemiological and experimental studies have demonstrated an association between impaired sleep and an increased risk of AD. These studies have led to the idea of a bidirectional relationship between AD and impaired sleep; in addition to the conventional concept that impaired sleep is a consequence of AD pathology, various evidence strongly suggests that impaired sleep is a risk factor for the initiation and progression of AD. Despite this recent progress, much remains to be elucidated in order to establish the benefit of therapeutic interventions against impaired sleep to prevent or alleviate the disease course of AD. In this review, we provide an overview of previous studies that have linked AD and sleep. We then highlight the studies that have tested the causal relationship between impaired sleep and AD and will discuss the molecular and cellular mechanisms underlying this link. We also propose future works that will aid the development of a novel disease-modifying therapy and prevention of AD via targeting impaired sleep through non-pharmacological and pharmacological interventions. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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15 pages, 455 KiB  
Review
Epigenetic Factors in Late-Onset Alzheimer’s Disease: MTHFR and CTH Gene Polymorphisms, Metabolic Transsulfuration and Methylation Pathways, and B Vitamins
by Gustavo C. Román, Oscar Mancera-Páez and Camilo Bernal
Int. J. Mol. Sci. 2019, 20(2), 319; https://doi.org/10.3390/ijms20020319 - 14 Jan 2019
Cited by 55 | Viewed by 13082
Abstract
DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer’s disease (LOAD). Methylenetetrahydrofolate reductase (MTHFR) gene mutations occur in most elderly patients with memory loss. MTHFR is critical for production of S-adenosyl-l-methionine (SAM), the principal [...] Read more.
DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer’s disease (LOAD). Methylenetetrahydrofolate reductase (MTHFR) gene mutations occur in most elderly patients with memory loss. MTHFR is critical for production of S-adenosyl-l-methionine (SAM), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase (CTH) gene affects the enzyme that converts cystathionine to cysteine in the transsulfuration pathway causing plasma elevation of total homocysteine (tHcy) or hyperhomocysteinemia—a strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors, and deficiencies of B vitamins. We emphasize the importance of supplementing vitamin B12 (methylcobalamin), vitamin B9 (folic acid), vitamin B6 (pyridoxine), and SAM to patients in early stages of LOAD. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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23 pages, 1367 KiB  
Review
Imaging and Molecular Mechanisms of Alzheimer’s Disease: A Review
by Grazia Daniela Femminella, Tony Thayanandan, Valeria Calsolaro, Klara Komici, Giuseppe Rengo, Graziamaria Corbi and Nicola Ferrara
Int. J. Mol. Sci. 2018, 19(12), 3702; https://doi.org/10.3390/ijms19123702 - 22 Nov 2018
Cited by 43 | Viewed by 8134
Abstract
Alzheimer’s disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to [...] Read more.
Alzheimer’s disease is the most common form of dementia and is a significant burden for affected patients, carers, and health systems. Great advances have been made in understanding its pathophysiology, to a point that we are moving from a purely clinical diagnosis to a biological one based on the use of biomarkers. Among those, imaging biomarkers are invaluable in Alzheimer’s, as they provide an in vivo window to the pathological processes occurring in Alzheimer’s brain. While some imaging techniques are still under evaluation in the research setting, some have reached widespread clinical use. In this review, we provide an overview of the most commonly used imaging biomarkers in Alzheimer’s disease, from molecular PET imaging to structural MRI, emphasising the concept that multimodal imaging would likely prove to be the optimal tool in the future of Alzheimer’s research and clinical practice. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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18 pages, 1202 KiB  
Review
Pin1 Modulation in Physiological Status and Neurodegeneration. Any Contribution to the Pathogenesis of Type 3 Diabetes?
by Marzia Bianchi and Melania Manco
Int. J. Mol. Sci. 2018, 19(8), 2319; https://doi.org/10.3390/ijms19082319 - 08 Aug 2018
Cited by 6 | Viewed by 5875
Abstract
Prolyl isomerases (Peptidylprolyl isomerase, PPIases) are enzymes that catalyze the isomerization between the cis/trans Pro conformations. Three subclasses belong to the class: FKBP (FK506 binding protein family), Cyclophilin and Parvulin family (Pin1 and Par14). Among Prolyl isomerases, Pin1 presents as distinctive [...] Read more.
Prolyl isomerases (Peptidylprolyl isomerase, PPIases) are enzymes that catalyze the isomerization between the cis/trans Pro conformations. Three subclasses belong to the class: FKBP (FK506 binding protein family), Cyclophilin and Parvulin family (Pin1 and Par14). Among Prolyl isomerases, Pin1 presents as distinctive feature, the ability of binding to the motif pSer/pThr-Pro that is phosphorylated by kinases. Modulation of Pin1 is implicated in cellular processes such as mitosis, differentiation and metabolism: The enzyme is dysregulated in many diverse pathological conditions, i.e., cancer progression, neurodegenerative (i.e., Alzheimer’s diseases, AD) and metabolic disorders (i.e., type 2 diabetes, T2D). Indeed, Pin1 KO mice develop a complex phenotype of premature aging, cognitive impairment in elderly mice and neuronal degeneration resembling that of the AD in humans. In addition, since the molecule modulates glucose homeostasis in the brain and peripherally, Pin1 KO mice are resistant to diet-induced obesity, insulin resistance, peripheral glucose intolerance and diabetic vascular dysfunction. In this review, we revise first critically the role of Pin1 in neuronal development and differentiation and then focus on the in vivo studies that demonstrate its pivotal role in neurodegenerative processes and glucose homeostasis. We discuss evidence that enables us to speculate about the role of Pin1 as molecular link in the pathogenesis of type 3 diabetes i.e., the clinical association of dementia/AD and T2D. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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26 pages, 1014 KiB  
Review
Recent Insights on Alzheimer’s Disease Originating from Yeast Models
by David Seynnaeve, Mara Del Vecchio, Gernot Fruhmann, Joke Verelst, Melody Cools, Jimmy Beckers, Daniel P. Mulvihill, Joris Winderickx and Vanessa Franssens
Int. J. Mol. Sci. 2018, 19(7), 1947; https://doi.org/10.3390/ijms19071947 - 03 Jul 2018
Cited by 26 | Viewed by 6298
Abstract
In this review article, yeast model-based research advances regarding the role of Amyloid-β (Aβ), Tau and frameshift Ubiquitin UBB+1 in Alzheimer’s disease (AD) are discussed. Despite having limitations with regard to intercellular and cognitive AD aspects, these models have clearly shown their [...] Read more.
In this review article, yeast model-based research advances regarding the role of Amyloid-β (Aβ), Tau and frameshift Ubiquitin UBB+1 in Alzheimer’s disease (AD) are discussed. Despite having limitations with regard to intercellular and cognitive AD aspects, these models have clearly shown their added value as complementary models for the study of the molecular aspects of these proteins, including their interplay with AD-related cellular processes such as mitochondrial dysfunction and altered proteostasis. Moreover, these yeast models have also shown their importance in translational research, e.g., in compound screenings and for AD diagnostics development. In addition to well-established Saccharomyces cerevisiae models, new upcoming Schizosaccharomyces pombe, Candida glabrata and Kluyveromyces lactis yeast models for Aβ and Tau are briefly described. Finally, traditional and more innovative research methodologies, e.g., for studying protein oligomerization/aggregation, are highlighted. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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11 pages, 702 KiB  
Review
Preventive Effects of Dairy Products on Dementia and the Underlying Mechanisms
by Yasuhisa Ano and Hiroyuki Nakayama
Int. J. Mol. Sci. 2018, 19(7), 1927; https://doi.org/10.3390/ijms19071927 - 30 Jun 2018
Cited by 37 | Viewed by 7855
Abstract
Alongside the rapid population aging occurring worldwide, the prevention of age-related memory decline and dementia has become a high priority. Dairy products have many physiological effects owing to their contents of lactic acid bacteria and the fatty acids and peptides generated during their [...] Read more.
Alongside the rapid population aging occurring worldwide, the prevention of age-related memory decline and dementia has become a high priority. Dairy products have many physiological effects owing to their contents of lactic acid bacteria and the fatty acids and peptides generated during their fermentation. In particular, several recent studies have elucidated the effects of fermented dairy products on cognitive function. Epidemiological and clinical evidence has indicated that fermented dairy products have preventive effects against dementia, including Alzheimer’s disease. Recent preclinical studies have identified individual molecules generated during fermentation that are responsible for those preventive effects. Oleamide and dehydroergosterol have been identified as the agents responsible for reducing microglial inflammatory responses and neurotoxicity. In this review, the protective effects of fermented dairy products and their components on cognitive function, the mechanisms underlying those effects, and the prospects for their future clinical development will be discussed. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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29 pages, 807 KiB  
Review
Cellular Receptors of Amyloid β Oligomers (AβOs) in Alzheimer’s Disease
by Barbara Mroczko, Magdalena Groblewska, Ala Litman-Zawadzka, Johannes Kornhuber and Piotr Lewczuk
Int. J. Mol. Sci. 2018, 19(7), 1884; https://doi.org/10.3390/ijms19071884 - 27 Jun 2018
Cited by 63 | Viewed by 7332
Abstract
It is estimated that Alzheimer’s disease (AD) affects tens of millions of people, comprising not only suffering patients, but also their relatives and caregivers. AD is one of age-related neurodegenerative diseases (NDs) characterized by progressive synaptic damage and neuronal loss, which result in [...] Read more.
It is estimated that Alzheimer’s disease (AD) affects tens of millions of people, comprising not only suffering patients, but also their relatives and caregivers. AD is one of age-related neurodegenerative diseases (NDs) characterized by progressive synaptic damage and neuronal loss, which result in gradual cognitive impairment leading to dementia. The cause of AD remains still unresolved, despite being studied for more than a century. The hallmark pathological features of this disease are senile plaques within patients’ brain composed of amyloid beta (Aβ) and neurofibrillary tangles (NFTs) of Tau protein. However, the roles of Aβ and Tau in AD pathology are being questioned and other causes of AD are postulated. One of the most interesting theories proposed is the causative role of amyloid β oligomers (AβOs) aggregation in the pathogenesis of AD. Moreover, binding of AβOs to cell membranes is probably mediated by certain proteins on the neuronal cell surface acting as AβO receptors. The aim of our paper is to describe alternative hypotheses of AD etiology, including genetic alterations and the role of misfolded proteins, especially Aβ oligomers, in Alzheimer’s disease. Furthermore, in this review we present various putative cellular AβO receptors related to toxic activity of oligomers. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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11 pages, 223 KiB  
Review
Presenilins as Drug Targets for Alzheimer’s Disease—Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development
by R. Scott Duncan, Bob Song and Peter Koulen
Int. J. Mol. Sci. 2018, 19(6), 1621; https://doi.org/10.3390/ijms19061621 - 31 May 2018
Cited by 18 | Viewed by 4032
Abstract
A major cause underlying familial Alzheimer’s disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the γ-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta [...] Read more.
A major cause underlying familial Alzheimer’s disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the γ-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta (Aβ). Consequently, presenilins have been the target of numerous and varied research efforts to develop therapeutic strategies for AD. The presenilin 1 gene harbors the largest number of AD-causing mutations resulting in the late onset familial form of AD. As a result, the majority of efforts for drug development focused on PS1 and Aβ. Soon after the discovery of the major involvement of PS1 and PS2 in γ-secretase activity, it became clear that neuronal signaling, particularly calcium ion (Ca2+) signaling, is regulated by presenilins and impacted by mutations in presenilin genes. Intracellular Ca2+ signaling not only controls the activity of neurons, but also gene expression patterns, structural functionality of the cytoskeleton, synaptic connectivity and viability. Here, we will briefly review the role of presenilins in γ-secretase activity, then focus on the regulation of Ca2+ signaling, oxidative stress, and cellular viability by presenilins within the context of AD and discuss the relevance of presenilins in AD drug development efforts. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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