An insight into Alzheimer’s disease and its on-setting novel genes

AbstractAccording to the World Health Organisation, as of 2019, globally around 50 million people suffer from dementia, with approximately another 10 million getting added to the list every year, wherein Alzheimer’s disease (AD) stands responsible for almost a whopping 60–70% for the existing number of cases. Alzheimer’s disease is one of the progressive, cognitive-declining, age-dependent, neurodegenerative diseases which is distinguished by histopathological symptoms, such as formation of amyloid plaque, senile plaque, neurofibrillary tangles, etc. Majorly four vital transcripts are identified in the AD complications which include Amyloid precursor protein (APP), Apolipoprotein E (ApoE), and two multi-pass transmembrane domain proteins—Presenilin 1 and 2. In addition, the formation of the abnormal filaments such as amyloid beta (Aβ) and tau and their tangling with some necessary factors contributing to the formation of plaques, neuroinflammation, and apoptosis which in turn leads to the emergence of AD. Although multiple molecular mechanisms have been elucidated so far, they are still counted as hypotheses ending with neuronal death on the basal forebrain and hippocampal area which results in AD. This review article is aimed at addressing the overview of the molecular mechanisms surrounding AD and the functional forms of the genes associated with it.

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Structural Studies Providing Insights into Production and Conformational Behavior of Amyloid-β Peptide Associated with Alzheimer’s Disease Development

Molecules ◽

10.3390/molecules26102897 ◽

2021 ◽

Vol 26 (10) ◽

pp. 2897

Author(s):

Anatoly S. Urban ◽

Konstantin V. Pavlov ◽

Anna V. Kamynina ◽

Ivan S. Okhrimenko ◽

Alexander S. Arseniev ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Transmembrane Domain ◽

Senile Plaques ◽

Amyloid Β ◽

Conformational Behavior ◽

Amyloid Β Peptide ◽

Structural Studies ◽

Aβ Production

Alzheimer’s disease is the most common type of neurodegenerative disease in the world. Genetic evidence strongly suggests that aberrant generation, aggregation, and/or clearance of neurotoxic amyloid-β peptides (Aβ) triggers the disease. Aβ accumulates at the points of contact of neurons in ordered cords and fibrils, forming the so-called senile plaques. Aβ isoforms of different lengths are found in healthy human brains regardless of age and appear to play a role in signaling pathways in the brain and to have neuroprotective properties at low concentrations. In recent years, different substances have been developed targeting Aβ production, aggregation, interaction with other molecules, and clearance, including peptide-based drugs. Aβ is a product of sequential cleavage of the membrane glycoprotein APP (amyloid precursor protein) by β- and γ-secretases. A number of familial mutations causing an early onset of the disease have been identified in the APP, especially in its transmembrane domain. The mutations are reported to influence the production, oligomerization, and conformational behavior of Aβ peptides. This review highlights the results of structural studies of the main proteins involved in Alzheimer’s disease pathogenesis and the molecular mechanisms by which perspective therapeutic substances can affect Aβ production and nucleation.

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Estrogen And Alzheimer's Disease: New Insights Into The Molecular Mechanisms Underlying The Increased Risk To Women.

PsycEXTRA Dataset ◽

10.1037/e322352004-025 ◽

2002 ◽

Author(s):

Karen Duff

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Increased Risk

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Faculty Opinions recommendation of Aspirin induces lysosomal biogenesis and attenuates amyloid plaque pathology in a mouse model of alzheimer's disease via pparα.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733575200.793548126 ◽

2018 ◽

Author(s):

Thierry Galli ◽

Alessandra Gallo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Amyloid Plaque ◽

Model Of Alzheimer’S Disease ◽

Plaque Pathology

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Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential

Current Pharmaceutical Design ◽

10.2174/1381612826666201112144006 ◽

2020 ◽

Vol 26 ◽

Author(s):

Nimra Javaid ◽

Muhammad Ajmal Shah ◽

Azhar Rasul ◽

Zunera Chauhdary ◽

Uzma Saleem ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Ellagic Acid ◽

Molecular Mechanisms ◽

Neurodegenerative Disorder ◽

Therapeutic Potential ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Acetylcholinesterase Activity ◽

Neuroprotective Effects

: Neurodegeneration is a multifactorial process involved the different cytotoxic pathways that lead towards neuronal cell death. Alzheimer’s disease (AD) is a persistent neurodegenerative disorder that normally has a steady onset yet later on it worsens. The documented evidence of AD neuropathology manifested the neuro-inflammation, increased reactive oxygen, nitrogen species and decreased antioxidant protective process; mitochondrial dysfunction as well as increased level of acetylcholinesterase activity. Moreover, enhanced action of proteins leads towards neural apoptosis which have a vital role in the degeneration of neurons. The inability of commercial therapeutic options to treat AD with targeting single mechanism leads the attraction towards organic drugs. Ellagic acid is a dimer of gallic acid, latest studies expressed that ellagic acid can initiate the numerous cell signaling transmission and decrease the progression of disorders, involved in the degeneration of neurons. The influential property of ellagic acid to protect the neurons in neurodegenerative disorders is due to its antioxidant effect, iron chelating and mitochondrial protective effect. The main goal of this review is to critically analyze the molecular mode of action of ellagic acid against neurodegeneration.

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Identifying Alzheimer’s Disease-related miRNA Based on Semi-clustering

Current Gene Therapy ◽

10.2174/1566523219666190924113737 ◽

2019 ◽

Vol 19 (4) ◽

pp. 216-223 ◽

Cited By ~ 2

Author(s):

Tianyi Zhao ◽

Donghua Wang ◽

Yang Hu ◽

Ningyi Zhang ◽

Tianyi Zang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drug Targets ◽

Molecular Mechanisms ◽

Feature Vector ◽

Mirna Gene ◽

Interaction Network ◽

Gene Interaction ◽

Proteinprotein Interaction ◽

Synaptic Structures

Background: More and more scholars are trying to use it as a specific biomarker for Alzheimer’s Disease (AD) and mild cognitive impairment (MCI). Multiple studies have indicated that miRNAs are associated with poor axonal growth and loss of synaptic structures, both of which are early events in AD. The overall loss of miRNA may be associated with aging, increasing the incidence of AD, and may also be involved in the disease through some specific molecular mechanisms. Objective: Identifying Alzheimer’s disease-related miRNA can help us find new drug targets, early diagnosis. Materials and Methods: We used genes as a bridge to connect AD and miRNAs. Firstly, proteinprotein interaction network is used to find more AD-related genes by known AD-related genes. Then, each miRNA’s correlation with these genes is obtained by miRNA-gene interaction. Finally, each miRNA could get a feature vector representing its correlation with AD. Unlike other studies, we do not generate negative samples randomly with using classification method to identify AD-related miRNAs. Here we use a semi-clustering method ‘one-class SVM’. AD-related miRNAs are considered as outliers and our aim is to identify the miRNAs that are similar to known AD-related miRNAs (outliers). Results and Conclusion: We identified 257 novel AD-related miRNAs and compare our method with SVM which is applied by generating negative samples. The AUC of our method is much higher than SVM and we did case studies to prove that our results are reliable.

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Characteristics of Insulin-degrading Enzyme in Alzheimer's Disease: A Meta-Analysis

Current Alzheimer Research ◽

10.2174/1567205015666180119105446 ◽

2018 ◽

Vol 15 (7) ◽

pp. 610-617 ◽

Cited By ~ 4

Author(s):

Huifeng Zhang ◽

Dan Liu ◽

Huanhuan Huang ◽

Yujia Zhao ◽

Hui Zhou

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Enzyme Activity ◽

Protein Level ◽

Senile Plaque ◽

Meta Analysis ◽

Cochrane Library ◽

Insulin Degrading Enzyme ◽

Degrading Enzyme ◽

Significant Difference

Background: β-amyloid (Aβ) accumulates abnormally to senile plaque which is the initiator of Alzheimer's disease (AD). As one of the Aβ-degrading enzymes, Insulin-degrading enzyme (IDE) remains controversial for its protein level and activity in Alzheimer's brain. Methods: The electronic databases PubMed, EMBASE, The Cochrane Library, OVID and Sinomed were systemically searched up to Sep. 20th, 2017. And the published case-control or cohort studies were retrieved to perform the meta-analysis. Results: Seven studies for IDE protein level (AD cases = 293; controls = 126), three for mRNA level (AD cases = 138; controls = 81), and three for enzyme activity (AD cases = 123; controls = 75) were pooling together. The IDE protein level was significantly lower in AD cases than in controls (SMD = - 0.47, 95% CI [-0.69, -0.24], p < 0.001), but IDE mRNA and enzyme activity had no significant difference (SMD = 0.02, 95% CI [-0.40, 0.43] and SMD = 0.06, 95% CI [-0.41, 0.53] respectively). Subgroup analyses found that IDE protein level was decreased in both cortex and hippocampus of AD cases (SMD = -0.43, 95% CI [-0.71, -0.16], p = 0.002 and SMD = -0.53, 95% CI [-0.91, -0.15], p = 0.006 respectively). However, IDE mRNA was higher in cortex of AD cases (SMD = 0.71, 95% CI [0.14, 1.29], p = 0.01), not in hippocampus (SMD = -0.26, 95% CI [-0.58, 0.06]). Conclusions: Our results indicate that AD patients may have lower IDE protease level. Further relevant studies are still needed to verify whether IDE is one of the factors affecting Aβ abnormal accumulation and throw new insights for AD detection or therapy.

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Targeting PPARalpha in Alzheimer's Disease

Current Alzheimer Research ◽

10.2174/1567205014666170505094549 ◽

2018 ◽

Vol 15 (4) ◽

pp. 345-354 ◽

Cited By ~ 13

Author(s):

Barbara D'Orio ◽

Anna Fracassi ◽

Maria Paola Cerù ◽

Sandra Moreno

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Mechanisms ◽

Redox Homeostasis ◽

Antioxidant Response ◽

Peroxisome Proliferator ◽

Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

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Biological Signatures of Alzheimer’s Disease

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200228095553 ◽

2020 ◽

Vol 20 (9) ◽

pp. 770-781 ◽

Cited By ~ 12

Author(s):

Poornima Sharma ◽

Anjali Sharma ◽

Faizana Fayaz ◽

Sharad Wakode ◽

Faheem H. Pottoo

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

Senile Plaque ◽

Senile Plaques ◽

Amyloid Deposition ◽

Immune Defense ◽

Amyloid Angiopathy ◽

Microvascular Changes ◽

Β Amyloid

Alzheimer’s disease (AD) is the most prevalent and severe neurodegenerative disease affecting more than 0.024 billion people globally, more common in women as compared to men. Senile plaques and amyloid deposition are among the main causes of AD. Amyloid deposition is considered as a central event which induces the link between the production of β amyloid and vascular changes. Presence of numerous biomarkers such as cerebral amyloid angiopathy, microvascular changes, senile plaques, changes in white matter, granulovascular degeneration specifies the manifestation of AD while an aggregation of tau protein is considered as a primary marker of AD. Likewise, microvascular changes, activation of microglia (immune defense system of CNS), amyloid-beta aggregation, senile plaque and many more biomarkers are nearly found in all Alzheimer’s patients. It was seen that 70% of Alzheimer’s cases occur due to genetic factors. It has been reported in various studies that apolipoprotein E(APOE) mainly APOE4 is one of the major risk factors for the later onset of AD. Several pathological changes also occur in the white matter which include dilation of the perivascular space, loss of axons, reactive astrocytosis, oligodendrocytes and failure to drain interstitial fluid. In this review, we aim to highlight the various biological signatures associated with the AD which may further help in discovering multitargeting drug therapy.

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Current Strategies and Novel Drug Approaches for Alzheimer Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200717091513 ◽

2020 ◽

Vol 19 (9) ◽

pp. 676-690 ◽

Cited By ~ 2

Author(s):

Roma Ghai ◽

Kandasamy Nagarajan ◽

Meenakshi Arora ◽

Parul Grover ◽

Nazakat Ali ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cholinergic Neurons ◽

Amyloid Plaque ◽

Neural Pathways ◽

Current Trends ◽

Personality Changes ◽

Traditional Therapies ◽

Novel Drug ◽

The Brain

Alzheimer’s Disease (AD) is a chronic, devastating dysfunction of neurons in the brain leading to dementia. It mainly arises due to neuronal injury in the cerebral cortex and hippocampus area of the brain and is clinically manifested as a progressive mental failure, disordered cognitive functions, personality changes, reduced verbal fluency and impairment of speech. The pathology behind AD is the formation of intraneuronal fibrillary tangles, deposition of amyloid plaque and decline in choline acetyltransferase and loss of cholinergic neurons. Tragically, the disease cannot be cured, but its progression can be halted. Various cholinesterase inhibitors available in the market like Tacrine, Donepezil, Galantamine, Rivastigmine, etc. are being used to manage the symptoms of Alzheimer’s disease. The paper’s objective is to throw light not only on the cellular/genetic basis of the disease, but also on the current trends and various strategies of treatment including the use of phytopharmaceuticals and nutraceuticals. Enormous literature survey was conducted and published articles of PubMed, Scifinder, Google Scholar, Clinical Trials.org and Alzheimer Association reports were studied intensively to consolidate the information on the strategies available to combat Alzheimer’s disease. Currently, several strategies are being investigated for the treatment of Alzheimer’s disease. Immunotherapies targeting amyloid-beta plaques, tau protein and neural pathways are undergoing clinical trials. Moreover, antisense oligonucleotide methodologies are being approached as therapies for its management. Phytopharmaceuticals and nutraceuticals are also gaining attention in overcoming the symptoms related to AD. The present review article concludes that novel and traditional therapies simultaneously promise future hope for AD treatment.

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