scholarly journals A Study of the SORL1 Gene in the Pathogenesis of Late-onset Alzheimer’s Disease by Affecting the Expression of BDNF

2021 ◽  
Author(s):  
Mingri Zhao ◽  
Jiangfeng Liu ◽  
Jingli He ◽  
Xun Chen ◽  
Yanjin Feng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Cell Model ◽  
Amyloid Β ◽  
Cognitive Disorders ◽  
Amyloid Β Protein ◽  
Bdnf Expression ◽  
The Brain

Abstract BackgroundAlzheimer’s disease is a neurodegenerative disease characterized by progressive memory impairment and other cognitive disorders. It is divided into Familial Alzheimer's disease (FAD) and Sporadic Alzheimer's disease (SAD). SAD is also called delayed Late-onset Alzheimer's disease (LOAD). Sortilin Related Receptor 1 (SORL1) is a high-risk pathogenic gene of LOAD, which can participate in the occurrence and development of AD by affecting the transport and metabolism of intracellular β-amyloid precursor protein (APP). The expression of SORL1 is significantly downregulated in patients with LOAD.ResultsIn the SORL1 knockout (SORL1 KO) mouse model constructed by CRISPR/cas9, we found that the expression of Brain Derived Neurotrophic Factor (BDNF) in the brain of SORL1 KO mice was significantly down-regulated and Amyloid β-protein (Aβ) deposition was found in the brain ofSORL1 KO mice. Through the SORL1 knockdown N2a cell model constructed by shRNA, we also found that when the SORL1 expression was knocked down, the BDNF expression was also downregulated and the cell viability decreased. The results of immunohistochemistry and in vitro cell model experiments suggest that the downregulation of BDNF caused by SORL1 knockdown may be mainly achieved by affecting the expression and distribution of N-Methyl-D-aspartate (NMDAR).ConclusionsSORL1 knockout changes the expression and distribution of NMDAR in cells, downregulates the expression of BDNF, and thus affects the learning and memory of mice.

MR Brain Screening using Optimization Techniques – A survey

2021 ◽  
Vol 17 ◽  
Author(s):  
Chitradevi D ◽  
Prabha S.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Memory Loss ◽  
Amyloid Β ◽  
Cell Loss ◽  
Optimization Techniques ◽  
Amyloid Β Protein ◽  
The Brain ◽  
Brain Tissues

Background: Alzheimer’s disease (AD) is associated with Dementia, and it is also a memory syndrome in the brain. It affects the brain tissues and causes major changes in day-to-day activities. Aging is a major cause of Alzheimer's disease. AD is characterized by two pathological hallmarks as, Amyloid β protein and neurofibrillary tangles of hyperphosphorylated tau protein. The imaging hallmarks for Alzheimer’s disease are namely, swelling, shrinkage of brain tissues due to cell loss, and atrophy in the brain due to protein dissemination. Based on the survey, 60% to 80% of dementia patients belong to Alzheimer’s disease. Introduction: AD is now becoming an increasing and important brain disease. The goal of AD pathology is to cause changes/damage in brain tissues. Alzheimer's disease is thought to begin 20 years or more before symptoms appear, with tiny changes in the brain that are undetectable to the person affected. The changes in a person's brain after a few years are noticeable through symptoms such as language difficulties and memory loss. Neurons in different parts of the brain have detected symptoms such as cognitive impairments and learning disabilities. In this case, neuroimaging tools are necessary to identify the development of pathology which relates to the clinical symptoms. Methods: Several approaches have been tried during the last two decades for brain screening to analyse AD with the process of pre-processing, segmentation and classification. Different individual such as Grey Wolf optimization, Lion Optimization, Ant Lion Optimization and so on. Similarly, hybrid optimization techniques are also attempted to segment the brain sub-regions which helps in identifying the bio-markers to analyse AD. Conclusion: This study discusses a review of neuroimaging technologies for diagnosing Alzheimer's disease, as well as the discovery of hallmarks for the disease and the methodologies for finding hallmarks from brain images to evaluate AD. According to the literature review, most of the techniques predicted higher accuracy (more than 90%), which is beneficial for assessing and screening neurodegenerative illness, particularly Alzheimer's disease.

scholarly journals Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer’s disease

2016 ◽  
Vol 8 (332) ◽  
pp. 332ra44-332ra44 ◽  
Author(s):  
Chia-Chen Liu ◽  
Na Zhao ◽  
Yu Yamaguchi ◽  
John R. Cirrito ◽  
Takahisa Kanekiyo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Therapeutic Interventions ◽  
Postmortem Human Brain ◽  
Aβ Clearance ◽  
Heparan Sulfates ◽  
The Brain

Accumulation of amyloid-β (Aβ) peptide in the brain is the first critical step in the pathogenesis of Alzheimer’s disease (AD). Studies in humans suggest that Aβ clearance from the brain is frequently impaired in late-onset AD. Aβ accumulation leads to the formation of Aβ aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in Aβ aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both Aβ oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of Aβ clearance in the brain interstitial fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting Aβ-HSPG interactions.

Commentary on: L-Methylfolate, Methylcobolamine, and N-Acetylcysteine in the Treatment of Alzheimer's Disease-Related Cognitive Decline

CNS Spectrums ◽  
2010 ◽  
Vol 15 (S1) ◽  
pp. 7-7 ◽  
Author(s):  
Jeffrey L Cummings
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Methylation Status ◽  
Neurofibrillary Tangle ◽  
Amyloid Β ◽  
Vitamin B ◽  
Amyloid Β Protein ◽  
In Vivo Models ◽  
The Impact

Drs. McCaddon and Hudson provide a thorough review of the multiple ways in which vitamin B12, vitamin B6, folate, and homocysteine (Hey) are implicated in the pathogenesis of Alzheimer's disease (AD). They noted that Hey is more often elevated in AD and in mild cognitive impairment (MCI) than in cognitively healthy elderly; phosphatases needed to limit tau hyperphosphoryalation and neurofibrillary tangle formation require methylation and are dependent on folate and methylation status; cerebrospinal fluid (CSF) tau levels correlated with markers of methylation status; reduced folate and B12 levels lead to increase β-secretase and pesenilin 1 (PS1) actions leading to greater amyloid-β production in in vitro models; elevated Hey levels in rates are associated with increased PS1 activity and spatial memory deficits that are reversed following treatment with B12 and folate; raised Hey levels in vitro increase amyloid-β protein neurotoxicity; methylation impacts transmitters and transmitter function relevant to AD; in cultured neurons, Hey induces injury in DNA and stimulates cell death pathways. B12 deficiency leads to accumulation of methyl malonic acid, which inhibits mitochondrial function and may compromise energy generation and impair maintenance of synaptic plasticity. Methylation abnormalities result in excessive generation of reactive oxygen species that contribute importantly to cell injury. Biomarkers of oxidative injury, such as isoprostanes, are elevated in AD and suggest excess oxidation. Thus, there are multiple pathways through which deficient methylation may contribute to AD. In some cases, the observations are derived from models with B12 or folate deficiency and some in vitro observations have not been tested in in vivo models. There are no biomarkers specific to some of the pathways implicated and the magnitude of the impact of the deficiency or its treatment has not been established for all the relationships. Two open-label experiments in early- and late-stage AD patients have suggested benefit.

scholarly journals Fibrillogenesis in Alzheimer's disease of amyloid β peptides and apolipoprotein E

1995 ◽  
Vol 306 (2) ◽  
pp. 599-604 ◽  
Author(s):  
E M Castano ◽  
F Prelli ◽  
T Wisniewski ◽  
A Golabek ◽  
R A Kumar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Tau Proteins ◽  
Amyloid Formation

A central event in Alzheimer's disease is the conformational change from normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neurofibrillary tangles respectively. The apolipoprotein E (apoE) gene locus has recently been associated with late-onset Alzheimer's disease. It is not know whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE can affect the known spontaneous in vitro formation of amyloid-like fibrils by synthetic A beta analogues using a thioflavine-T assay for fibril formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid fibril formation, increasing both the rate of fibrillogenesis and the total amount of amyloid formed. ApoE accelerated fibril formation of both wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replacement of valine with alanine at residue 18, which alone produces few amyloid-like fibrils. However, apoE produced only a minimal effect on A beta-(1-40Q), found in the Dutch variant of Alzheimer's disease. When recombinant apoE isoforms were used, apoE4 was more efficient than apoE3 at enhancing amyloid formation. These in vitro observations support the hypothesis that apoE acts as a pathological chaperone, promoting the beta-pleated-sheet conformation of soluble A beta into amyloid fibres, and provide a possible explanation for the association of the apoE4 genetic isoform with Alzheimer's disease.

scholarly journals The glymphatic system and its role in the development of Alzheimer’s disease

2021 ◽  
Vol 8 (3) ◽  
pp. 14-21
Author(s):  
S. V. Vorobʼev ◽  
S. N. Yanishevskij
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Picture ◽  
Amyloid Β ◽  
Cognitive Disorders ◽  
Comprehensive Analysis ◽  
Synaptic Dysfunction ◽  
Glymphatic System ◽  
Neurodegenerative Pathology ◽  
The Brain

One of the main concepts explaining the development of Alzheimer’s disease is currently the amyloid theory. It was reliably established that the accumulation of the pathological protein amyloid β provokes the launch of a number of pathochemical reactions that ultimately lead to the development of synaptic dysfunction and the formation of cognitive disorders. The protein amyloid β is also synthesized in the brain of people who do not suffer from neurodegenerative pathology. Normally, it is actively removed from the brain. However, the exact mechanisms for maintaining its clearance are not established. The recently discovered glymphatic system claims to be such a component. The present review provides a comprehensive analysis of suggestions that the development of glymphatic system dysfunction contributes to the accumulation of amyloid β and the development of the clinical picture of Alzheimer›s disease.

scholarly journals Upregulation of Alzheimer’s Disease Amyloid-β Protein Precursor in Astrocytes Both in vitro and in vivo

2020 ◽  
pp. 1-12 ◽  
Author(s):  
Yingxia Liang ◽  
Frank Raven ◽  
Joseph F. Ward ◽  
Sherri Zhen ◽  
Siyi Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein

scholarly journals Plant sphingolipids promote extracellular vesicle release and alleviate amyloid-β pathologies in a mouse model of Alzheimer’s disease

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kohei Yuyama ◽  
Kaori Takahashi ◽  
Seigo Usuki ◽  
Daisuke Mikami ◽  
Hui Sun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Neuronal Cultures ◽  
Amyloid Β Protein ◽  
Neuronal Marker ◽  
Enhanced Production ◽  
Model Of Alzheimer’S Disease ◽  
Aβ Clearance

AbstractThe accumulation of amyloid-β protein (Aβ) in brain is linked to the early pathogenesis of Alzheimer’s disease (AD). We previously reported that neuron-derived exosomes promote Aβ clearance in the brains of amyloid precursor protein transgenic mice and that exosome production is modulated by ceramide metabolism. Here, we demonstrate that plant ceramides derived from Amorphophallus konjac, as well as animal-derived ceramides, enhanced production of extracellular vesicles (EVs) in neuronal cultures. Oral administration of plant glucosylceramide (GlcCer) to APP overexpressing mice markedly reduced Aβ levels and plaque burdens and improved cognition in a Y-maze learning task. Moreover, there were substantial increases in the neuronal marker NCAM-1, L1CAM, and Aβ in EVs isolated from serum and brain tissues of the GlcCer-treated AD model mice. Our data showing that plant ceramides prevent Aβ accumulation by promoting EVs-dependent Aβ clearance in vitro and in vivo provide evidence for a protective role of plant ceramides in AD. Plant ceramides might thus be used as functional food materials to ameliorate AD pathology.

A Chronological Review of Potential Disease-Modifying Therapeutic Strategies for Alzheimer's Disease

2020 ◽  
Vol 26 (12) ◽  
pp. 1286-1299 ◽  
Author(s):  
Miren Ettcheto ◽  
Oriol Busquets ◽  
Triana Espinosa-Jiménez ◽  
Ester Verdaguer ◽  
Carme Auladell ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Wide Spectrum ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
New Therapeutic Approaches ◽  
Β Protein

: Late-onset Alzheimer’s disease (LOAD) is a neurodegenerative disorder that has become a worldwide health problem. This pathology has been classically characterized for its affectation on cognitive function and the presence of depositions of extracellular amyloid β-protein (Aβ) and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated Tau protein. To this day, no effective treatment has been developed. : Multiple strategies have been proposed over the years with the aim of finding new therapeutic approaches, such as the sequestration of Aβ in plasma or the administration of anti-inflammatory drugs. Also, given the significant role of the insulin receptor in the brain in the proper maintenance of cognitive function, drugs focused on the amelioration of insulin resistance have been proposed as potentially useful and effective in the treatment of AD. In the present review, taking into account the molecular complexity of the disease, it has been proposed that the most appropriate therapeutic strategy is a combinatory treatment of several drugs that will regulate a wide spectrum of the described altered pathological pathways.

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