scholarly journals RGS2 expression predicts amyloid-β sensitivity, MCI and Alzheimer’s disease: genome-wide transcriptomic profiling and bioinformatics data mining

2016 ◽  
Vol 6 (10) ◽  
pp. e909-e909 ◽  
Author(s):  
A Hadar ◽  
E Milanesi ◽  
A Squassina ◽  
P Niola ◽  
C Chillotti ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Data Mining ◽  
Alzheimer's Disease ◽  
G Protein ◽  
Amyloid Β ◽  
Healthy Individuals ◽  
Transcriptomic Profiling ◽  
Expression Levels ◽  
Genome Wide ◽  
Lower Expression

Abstract Alzheimer's disease (AD) is the most frequent cause of dementia. Misfolded protein pathological hallmarks of AD are brain deposits of amyloid-β (Aβ) plaques and phosphorylated tau neurofibrillary tangles. However, doubts about the role of Aβ in AD pathology have been raised as Aβ is a common component of extracellular brain deposits found, also by in vivo imaging, in non-demented aged individuals. It has been suggested that some individuals are more prone to Aβ neurotoxicity and hence more likely to develop AD when aging brains start accumulating Aβ plaques. Here, we applied genome-wide transcriptomic profiling of lymphoblastoid cells lines (LCLs) from healthy individuals and AD patients for identifying genes that predict sensitivity to Aβ. Real-time PCR validation identified 3.78-fold lower expression of RGS2 (regulator of G-protein signaling 2; P=0.0085) in LCLs from healthy individuals exhibiting high vs low Aβ sensitivity. Furthermore, RGS2 showed 3.3-fold lower expression (P=0.0008) in AD LCLs compared with controls. Notably, RGS2 expression in AD LCLs correlated with the patients’ cognitive function. Lower RGS2 expression levels were also discovered in published expression data sets from postmortem AD brain tissues as well as in mild cognitive impairment and AD blood samples compared with controls. In conclusion, Aβ sensitivity phenotyping followed by transcriptomic profiling and published patient data mining identified reduced peripheral and brain expression levels of RGS2, a key regulator of G-protein-coupled receptor signaling and neuronal plasticity. RGS2 is suggested as a novel AD biomarker (alongside other genes) toward early AD detection and future disease modifying therapeutics.

Detection of amyloid β protein in the urine of Alzheimer's disease patients and healthy individuals

2008 ◽  
Vol 435 (2) ◽  
pp. 126-130 ◽  
Author(s):  
Manabu Takata ◽  
Manabu Nakashima ◽  
Taro Takehara ◽  
Hideyo Baba ◽  
Kazuyuki Machida ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Healthy Individuals ◽  
Β Protein

Tooth Loss Induces Memory Impairment and Gliosis in App Knock-In Mouse Models of Alzheimer’s Disease

2021 ◽  
Vol 80 (4) ◽  
pp. 1687-1704
Author(s):  
Ferdous Taslima ◽  
Cha-Gyun Jung ◽  
Chunyu Zhou ◽  
Mona Abdelhamid ◽  
Mohammad Abdullah ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mrna Expression ◽  
Neuronal Activity ◽  
Memory Impairment ◽  
Tooth Loss ◽  
Amyloid Β ◽  
Glial Activation ◽  
Expression Levels ◽  
Mrna Expression Levels

Background: Epidemiological studies have shown that tooth loss is associated with Alzheimer’s disease (AD) and dementia. However, the molecular and cellular mechanisms by which tooth loss causes AD remain unclear. Objective: We investigated the effects of tooth loss on memory impairment and AD pathogenesis in AppNL-G-F mice. Methods: Maxillary molar teeth on both sides were extracted from 2-month-old AppNL-G-F mice, and the mice were reared for 2 months. The short- and long-term memory functions were evaluated using a novel object recognition test and a passive avoidance test. Amyloid plaques, amyloid-β (Aβ) levels, glial activity, and neuronal activity were evaluated by immunohistochemistry, Aβ ELISA, immunofluorescence staining, and western blotting. The mRNA expression levels of neuroinflammatory cytokines were determined by qRT-PCR analysis. Results: Tooth loss induced memory impairment via an amyloid-cascade-independent pathway, and decreased the neuronal activity, presynaptic and postsynaptic protein levels in both the cortex and hippocampus. Interestingly, we found that tooth loss induced glial activation, which in turn leads to the upregulation of the mRNA expression levels of the neuroinflammation cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in the hippocampus. We also found that tooth loss activated a stress-activated protein kinase, c-Jun N-terminal kinase (JNK), and increased heat shock protein 90 (HSP90) levels in the hippocampus, which may lead to a glial activation. Conclusion: Our findings suggest that taking care of teeth is very important to preserve a healthy oral environment, which may reduce the risk of cognitive dysfunction.

scholarly journals Data Mining of Molecular Simulations Suggest Key Amino Acid Residues for Aggregation, Signaling and Drug Action

Biomolecules ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1541
Author(s):  
Vaibhav Gurunathan ◽  
John Hamre Hamre ◽  
Dmitri K. Klimov ◽  
Mohsin Saleet Jafri
Keyword(s):  
Alzheimer’S Disease ◽  
Data Mining ◽  
Alzheimer's Disease ◽  
Molecular Simulation ◽  
Confusion Matrix ◽  
Amyloid Β ◽  
Md Simulations ◽  
Machine Learning Techniques ◽  
Data Set ◽  
Specificity And Sensitivity

Alzheimer’s disease, the most common form of dementia, currently has no cure. There are only temporary treatments that reduce symptoms and the progression of the disease. Alzheimer’s disease is characterized by the prevalence of plaques of aggregated amyloid β (Aβ) peptide. Recent treatments to prevent plaque formation have provided little to relieve disease symptoms. Although there have been numerous molecular simulation studies on the mechanisms of Aβ aggregation, the signaling role has been less studied. In this study, a total of over 38,000 simulated structures, generated from molecular dynamics (MD) simulations, exploring different conformations of the Aβ42 mutants and wild-type peptides were used to examine the relationship between Aβ torsion angles and disease measures. Unique methods characterized the data set and pinpointed residues that were associated in aggregation and others associated with signaling. Machine learning techniques were applied to characterize the molecular simulation data and classify how much each residue influenced the predicted variant of Alzheimer’s Disease. Orange3 data mining software provided the ability to use these techniques to generate tables and rank the data. The test and score module coupled with the confusion matrix module analyzed data with calculations of specificity and sensitivity. These methods evaluating frequency and rank allowed us to analyze and predict important residues associated with different phenotypic measures. This research has the potential to help understand which specific residues of Aβ should be targeted for drug development.

Multiomics Investigation of Hypertension and White Matter Hyperintensity as a Source of Vascular Dementia or a Comorbidity to Alzheimer’s Disease

2021 ◽  
Vol 18 ◽  
Author(s):  
Gita A. Pathak ◽  
Robert C. Barbe ◽  
Nicole R. Phillips
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vascular Dementia ◽  
Amyloid Β ◽  
The Elderly ◽  
White Matter Hyperintensity ◽  
P Value ◽  
Csf Biomarkers ◽  
Age Related ◽  
Genome Wide

Background: Age-related comorbidity is common and significantly increases the burden for the healthcare of the elderly. Alzheimer’s disease (AD) and hypertension are the two most prevalent age-related conditions and are highly comorbid. While hypertension is a risk factor for vascular dementia (VD), hypertension with AD (ADHyp+) is often characterized as probable vascular dementia. In the absence of imaging and other diagnostic tests, differentiating the two pathological states is difficult. Objective: Our goals are to (1) identify differences in CSF-based vascular dementia profiles, if any, between individuals who have AD only (ADHyp-), and individuals with ADHyp+ using CSF levels of amyloid β, tau and p-tau, and (2) compare genome-wide DNA profiles of ADHyp- and AD-Hyp+ with an unaffected control population. Methods: Genotype and clinical data were used to compare healthy controls to AD+/Hyp- vs AD+/Hyp+. We compared the CSF biomarkers followed by evaluating genome wide profiles in three groups, and mapped SNPs to genes based on position and lowest p-value. The significant genes were examined for co-expression and known disease networks. Results: We found no differences between Aβ, tau and p-tau levels between ADHyp- and AD- Hyp+. We found TOMM40 to be associated with ADHyp- as expected but not with ADHyp+. Inter- estingly, SLC9A3R2 polymorphism was associated with ADHyp+, and significant gene expression changes were observed for neighboring genes. Conclusion: Through this exploratory study using a novel cohort stratification design, we highlight the genetic differences in clinically similar phenotypes, indicating the utility of genetic profiling in aiding differential diagnosis of ADHyp+ and VD.

scholarly journals A histone acetylome-wide association study of Alzheimer’s disease: neuropathology-associated regulatory variation in the human entorhinal cortex

2017 ◽  
Author(s):  
Sarah J. Marzi ◽  
Teodora Ribarska ◽  
Adam R. Smith ◽  
Eilis Hannon ◽  
Jeremie Poschmann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Entorhinal Cortex ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Association Studies ◽  
Amyloid Β ◽  
Genomic Variation ◽  
Genome Wide Association Studies ◽  
Genome Wide

AbstractAlzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by the progressive accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles in the neocortex. Recent studies have implicated a role for regulatory genomic variation in AD progression, finding widespread evidence for altered DNA methylation associated with neuropathology. To date, however, no study has systematically examined other types of regulatory genomic modifications in AD. In this study, we quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - in entorhinal cortex samples from AD cases and matched controls (n = 47) using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). Across ~182,000 robustly detected H3K27ac peak regions, we found widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 0.05) between AD cases and controls. These differentially acetylated peaks are enriched in disease-specific biological pathways and include regions annotated to multiple genes directly involved in the progression of Aβ and tau pathology (e.g. APP, PSEN1, PSEN2, MAPT), as well as genomic regions containing variants associated with sporadic late-onset AD. This is the first study of variable H3K27ac yet undertaken in AD and the largest study investigating this modification in the entorhinal cortex. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease, integrating our data with results obtained from genome-wide association studies as well as other epigenetic marks profiled on the same samples.

scholarly journals G-protein coupled receptor, PI3K and Rho signaling pathways regulate the cascades of Tau and amyloid-β in Alzheimer’s disease

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Smita Eknath Desale ◽  
Hariharakrishnan Chidambaram ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
G Protein ◽  
Tau Protein ◽  
Amyloid Β ◽  
Small Gtpases ◽  
Gpcr Signaling ◽  
G Protein Coupled

AbstractAlzheimer’s disease is a progressive neurodegenerative disease characterized by the presence of amyloid-β plaques in the extracellular environment and aggregates of Tau protein that forms neurofibrillary tangles (NFTs) in neuronal cells. Along with these pathological proteins, the disease shows neuroinflammation, neuronal death, impairment in the immune function of microglia and synaptic loss, which are mediated by several important signaling pathways. The PI3K/Akt-mediated survival-signaling pathway is activated by many receptors such as G-protein coupled receptors (GPCRs), triggering receptor expressed on myeloid cells 2 (TREM2), and lysophosphatidic acid (LPA) receptor. The signaling pathway not only increases the survival of neurons but also regulates inflammation, phagocytosis, cellular protection, Tau phosphorylation and Aβ secretion as well. In this review, we focused on receptors, which activate PI3K/Akt pathway and its potential to treat Alzheimer’s disease. Among several membrane receptors, GPCRs are the major drug targets for therapy, and GPCR signaling pathways are altered during Alzheimer’s disease. Several GPCRs are involved in the pathogenic progression, phosphorylation of Tau protein by activation of various cellular kinases and are involved in the amyloidogenic pathway of amyloid-β synthesis. Apart from various GPCR signaling pathways, GPCR regulating/ interacting proteins are involved in the pathogenesis of Alzheimer’s disease. These include several small GTPases, Ras homolog enriched in brain, GPCR associated sorting proteins, β-arrestins, etc., that play a critical role in disease progression and has been elaborated in this review.

Sign in / Sign up

Export Citation Format

Share Document