scholarly journals Significant Associations of the Interplay Between Stress Related Genes With Alzheimer’s Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 640-641
Author(s):  
Anatoliy Yashin ◽  
Deqing Wu ◽  
Konstantin Arbeev ◽  
Olivia Bagley ◽  
Igor Akushevich ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stress Response ◽  
Cellular Stress ◽  
Experimental Studies ◽  
Cellular Stress Response ◽  
Disease Stage ◽  
Preclinical Ad ◽  
Stress Signals ◽  
Stress Related Genes

Abstract The lack of efficient medication against Alzheimer’s disease (AD) is the most important problem for this health disorder today. One possible reason for this -- the implementing medical interventions “too late in the disease stage” – has been recently addressed in the initiative that defined the preclinical AD stage by measuring changes in preclinical AD biomarkers. According to this definition, beta amyloid (Aβ) is one of the key preclinical AD biomarkers. Experimental studies showed that Aβ results from proteolytic cleavage of APP by β- and γ-secretases. Production of β-secretase involves BACE1 gene, activated by cellular stress response. This suggest that AD might be initiated by cellular stressors and that multifactorial regulation of AD is likely to be driven by genes involved in cellular stress response. In this paper we investigate whether interplay between SNPs from the EIF2AK4 gene involved in sensing cellular stress signals and the APP gene dealing with Aβ production may be associated with AD in human data. For this, we evaluated association of the interactions of the pairs of SNPs from these genes with AD in the analysis of HRS data. We found that interactions between several SNPs have statistically significant associations with AD. The results of this analysis confirm that the interplay between gene served as a sensor of cellular stress and gene involved in production of preclinical AD biomarker in response to stress may influence human AD. This analysis illustrates an important step towards translation of the results of experimental AD studies to human applications.

Nitrosative Stress, Cellular Stress Response, and Thiol Homeostasis in Patients with Alzheimer's Disease

2006 ◽  
Vol 8 (11-12) ◽  
pp. 1975-1986 ◽  
Author(s):  
Vittorio Calabrese ◽  
Rukhsana Sultana ◽  
Giovanni Scapagnini ◽  
Eleonora Guagliano ◽  
Maria Sapienza ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stress Response ◽  
Nitrosative Stress ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Thiol Homeostasis

scholarly journals Mechanisms of functional compensation, delineated by eigenvector centrality mapping, across the pathophysiological continuum of Alzheimer's disease.

2018 ◽  
Author(s):  
Stavros Skouras ◽  
Carles Falcon ◽  
Alan Tucholka ◽  
Lorena Rami ◽  
Raquel Sanchez-Valle ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Functional Connectivity ◽  
Memory Performance ◽  
Disease Stage ◽  
Eigenvector Centrality ◽  
Whole Brain ◽  
Functional Compensation ◽  
Mild Dementia ◽  
Preclinical Ad

Background: Mechanisms of functional compensation throughout the progression of Alzheimer's disease (AD) remain largely underspecified. By investigating functional connectomics in relation to cerebrospinal fluid (CSF) biomarkers across the pathophysiological continuum of AD, we identify disease-stage-specific patterns of functional degradation and functional compensation. Methods: Data from a sample of 96 participants, comprised of 49 controls, 11 preclinical AD subjects, 21 patients with mild cognitive impairment (MCI) due to AD and 15 patients with mild dementia due to AD, were analyzed. CSF ratio of phosphorylated tau protein over amyloid beta peptide 42 (p-tau/Aβ42) was computed and used as a marker of progression along the AD continuum. Whole-brain, voxel-wise eigenvector centrality mapping (ECM) was computed from resting-state fMRI and regression against p-tau/Aβ42 was performed. Surviving clusters were used as data-derived seeds in functional connectivity analyses and investigated in relation to memory performance scores (delayed free recall and memory alteration) via complementary regression models. To investigate disease-stage-specific effects, the whole-brain connectivity maps of each cluster were compared between progressive groups. Results: Decreasing centrality in the inferior parietal lobule (IPL) is significantly correlated with the p-tau/Aβ42 ratio and associated to memory function impairment across the AD continuum. The thalamus, anterior cingulate (ACC), midcingulate (MCC) and posterior cingulate cortex (PCC) show the opposite effect. The MCC shows the highest increase in centrality as memory performance decays. In the asymptomatic preclinical group, MCC shows reduced functional connectivity (FC) with the left hippocampus and stronger FC with the precuneus (PCu). Additionally, IPL shows reduced FC with the cerebellum, compensated by stronger FC between cerebellum and PCC. In the MCI group, PCC shows reduced FC with PCu, compensated by stronger FC with the left pars orbitalis, insula and temporal pole, as well as by stronger FC of MCC with its anterior and ventral neighboring areas and the cerebellum. In the mild dementia group, extensive functional decoupling occurs across the entire autobiographical memory network and functional resilience ensues in posterior regions and the cerebellum. Conclusions: Functional decoupling in preclinical AD occurs predominantly in AD-vulnerable regions (e.g. hippocampus, cerebellar lobule VI / Crus I, visual cortex, frontal pole) and coupling between MCC and PCu, as well as between PCC and cerebellum, emerge as intrinsic mechanisms of functional compensation. At the MCI stage, the PCu can no longer compensate for hippocampal decoupling, but the compensatory role of the MCC and PCC ensue into the stage of dementia. These findings shed light on the neural mechanisms of functional compensation across the pathophysiological continuum of AD, highlighting the compensatory roles of several key brain areas.

Microglia in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Patrick Süß ◽  
Johannes C.M. Schlachetzki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
Disease Stage ◽  
Disease Modifying Therapy ◽  
Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

Identification of a Pathogenic PSEN1 Ala285Val Mutation Associated with Early-Onset Alzheimer’s Disease

2020 ◽  
Vol 17 (5) ◽  
pp. 438-445
Author(s):  
Van Giau Vo ◽  
Jung-Min Pyun ◽  
Eva Bagyinszky ◽  
Seong S.A. An ◽  
Sang Y. Kim
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Temporal Lobe ◽  
Early Onset ◽  
Parietal Lobe ◽  
Disease Diagnosis ◽  
Random Coil ◽  
Magnetic Resonance Imaging Scan ◽  
Preclinical Ad ◽  
Early Onset Alzheimer’S Disease

Background: Presenilin 1 (PSEN1) was suggested as the most common causative gene of early onset Alzheimer’s Disease (AD). Methods: Patient who presented progressive memory decline in her 40s was enrolled in this study. A broad battery of neuropsychological tests and neuroimaging was applied to make the diagnosis. Genetic tests were performed in the patient to evaluate possible mutations using whole exome sequencing. The pathogenic nature of missense mutation and its 3D protein structure prediction were performed by in silico prediction programs. Results: A pathogenic mutation in PSEN1 (NM_000021.3: c.1027T>C p.Ala285Val), which was found in a Korean EOAD patient. Magnetic resonance imaging scan showed mild left temporal lobe atrophy. Hypometabolism appeared through 18F-fludeoxyglucose Positron Emission Tomography (FDG-PET) scanning in bilateral temporal and parietal lobe, and 18F-Florbetaben-PET (FBB-PET) showed increased amyloid deposition in bilateral frontal, parietal, temporal lobe and hence presumed preclinical AD. Protein modeling showed that the p.Ala285Val is located in the random coil region and could result in extra stress in this region, resulting in the replacement of an alanine residue with a valine. This prediction was confirmed previous in vitro studies that the p.Trp165Cys resulted in an elevated Aβ42/Aβ40 ratio in both COS-1 and HEK293 cell lines compared that of wild-type control. Conclusion: Together, the clinical characteristics and the effect of the mutation would facilitate our understanding of PSEN1 in AD pathogenesis for the disease diagnosis and treatment. Future in vivo study is needed to evaluate the role of PSEN1 p.Ala285Val mutation in AD progression.

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