scholarly journals Genetic variants associated with Alzheimer's disease confer different cerebral cortex cell-type population structure

2018 ◽  
Author(s):  
Zeran Li ◽  
Jorge L Del-Aguila ◽  
Umber Dube ◽  
John Budde ◽  
Rita Martinez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Cortex ◽  
Genetic Risk ◽  
Molecular Mechanisms ◽  
Neuronal Loss ◽  
Reference Panel ◽  
Cellular Composition ◽  
Cell Type ◽  
Large Bulk

AbstractAlzheimer’s disease (AD) is characterized by neuronal loss and astrocytosis in the cerebral cortex. However, the effects of brain cellular composition are often ignored in high-throughput molecular studies. We developed and optimized a cell-type specific expression reference panel and employed digital deconvolution methods to determine brain cellular distribution in three independent transcriptomic studies. We found that neuronal and astrocyte proportions differ between healthy and diseased brains and also among AD cases that carry specific genetic risk variants. Brain carriers of pathogenic mutations in APP, PSEN1 or PSEN2 presented lower neurons and higher astrocytes proportions compared to sporadic AD. Similarly, the APOE ε4 allele also showed decreased neurons and increased astrocytes compared to AD non-carriers. On the contrary, carriers of variants in TREM2 risk showed a lower degree of neuronal loss than matched AD cases in multiple independent studies. These findings suggest that genetic risk factors associated with AD etiology have a specific imprinting in the cellular composition of AD brains. Our digital deconvolution reference panel provides an enhanced understanding of the fundamental molecular mechanisms underlying neurodegeneration, enabling the analysis of large bulk RNA-seq studies for cell composition, and suggests that correcting for the cellular structure when performing transcriptomic analysis will lead to novel insights of AD.

scholarly journals Genetic variants associated with Alzheimer’s disease confer different cerebral cortex cell-type population structure

2018 ◽  
Vol 10 (1) ◽  
Author(s):  
Zeran Li ◽  
◽  
Jorge L. Del-Aguila ◽  
Umber Dube ◽  
John Budde ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Population Structure ◽  
Cerebral Cortex ◽  
Genetic Variants ◽  
Cell Type ◽  
Cortex Cell ◽  
Type Population

scholarly journals Mechanisms of Neuronal Death in the Cerebral Cortex during Aging and Development of Alzheimer’s Disease-Like Pathology in Rats

2019 ◽  
Vol 20 (22) ◽  
pp. 5632 ◽  
Author(s):  
Darya V. Telegina ◽  
Gleb K. Suvorov ◽  
Oyuna S. Kozhevnikova ◽  
Nataliya G. Kolosova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Decision Making ◽  
Cell Death ◽  
Cerebral Cortex ◽  
Brain Development ◽  
Brain Region ◽  
Neuronal Death ◽  
Neuronal Loss ◽  
Decision Making Behavior

Alzheimer’s disease (AD) is the commonest type of late-life dementia and damages the cerebral cortex, a vulnerable brain region implicated in memory, emotion, cognition, and decision-making behavior. AD is characterized by progressive neuronal loss, but the mechanisms of cell death at different stages of the disease remain unknown. Here, by means of OXYS rats as an appropriate model of the most common (sporadic) AD form, we studied the main pathways of cell death during development of AD-like pathology, including the preclinical stage. We found that apoptosis is activated at the pre-symptomatic stage (age 20 days) correlating with the retardation of brain development in the OXYS strain early in life. Progression of the AD-like pathology was accompanied by activation of apoptosis and necroptosis resulting from a decline of autophagy-mediated proteostasis. Our results are consistent with the idea that the nature of changes in the pathways of apoptosis, autophagy, and necrosis depends on the stage of AD.

scholarly journals Combinatorial analyses reveal cellular composition changes have different impacts on transcriptomic changes of cell type specific genes in Alzheimer’s Disease

2020 ◽  
Author(s):  
Travis S. Johnson ◽  
Shunian Xiang ◽  
Tianhan Dong ◽  
Zhi Huang ◽  
Michael Cheng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Activation ◽  
Cellular Composition ◽  
Cell Type ◽  
Tissue Samples ◽  
Deconvolution Analysis ◽  
Neuron Loss ◽  
Transcriptomic Changes ◽  
Composition Changes

Abstract Alzheimer’s disease (AD) brains are characterized by progressive neuron loss and gliosis. Previous studies comparing AD versus control using bulk brain tissue samples have not considered cell composition changes in AD brains that can cause transcriptional changes not due to transcriptional regulation.Using five large transcriptomic datasets, we mined conserved gene co-expression network modules, and applied differential expression and differential co-expression analysis on the modules in AD versus control brains. Combined with cell type deconvolution analysis, we addressed the question of whether the module expression changes are due to altered cellular composition or transcriptional regulation. Our findings were validated using four additional datasets.We discovered that the increased expression of microglia modules can be explained by increased microglia population in AD brains rather than gene upregulation. In contrast, the decreased expression and perturbed co-expression in AD neuron modules are due to both neuron loss and regulation of neuronal pathways and several transcriptional factors are identified for such regulation. Similarly, the strong changes in expression and co-expression in astrocyte modules can also be attributed to a combinatory effect from astrogliosis and astrocyte gene activation in AD brains. The astrocyte modules expressions also strongly correlated with the clinicopathological biomarkers.In summary, we demonstrated that combinatorial analysis is a powerful approach to delineate the origin of transcriptomic changes in bulk tissue data, which leads to a deeper understanding of key genes/pathways in AD.

scholarly journals Combinatorial analyses reveal that cellular composition changes have different impact on transcriptomic changes of cell type specific genes in Alzheimer’s Disease brains

2020 ◽  
Author(s):  
Shunian Xiang ◽  
Travis Johnson ◽  
Tianhan Dong ◽  
Zhi Huang ◽  
Michael Cheng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transcriptional Regulation ◽  
Brain Tissue ◽  
Cellular Composition ◽  
Cell Type ◽  
Tissue Samples ◽  
Cell Type Specific ◽  
Transcriptomic Changes ◽  
Composition Changes

Abstract Background Alzheimer’s disease (AD) brains are characterized by progressive neuron loss and gliosis which involves mostly microglia and astrocytes. Comparative transcriptomic analysis on AD vs. normal brain tissues helps to identify key genes/pathways involved in AD initiation and progression. However, many such studies using bulk brain tissue samples have not considered cell composition changes in AD brains, which may lead to expression changes that are not due to transcriptional regulation. Methods Using five large transcriptomic datasets including 1,681 brain tissue samples (882 AD, 799 normal) in total, we first mined frequent co-expression network modules across them, then combined differential expression and differential co-expression analysis on the mined modules in AD versus normal brains. Integrated with cell type deconvolution analysis, we addressed the question of whether the module expression changes are due to altered cellular composition or transcriptional regulation. We then used four additional large AD/normal transcriptomic datasets to validate our findings. Results The integrative analysis revealed highly elevated expression level of microglia modules in AD without co-expression change. Decreased expression and elevated co-expression are observed for neuron modules in AD, while significant over-expression and co-expression perturbation are observed in astrocyte modules, all of which has not been previously reported. The expression levels of astrocyte modules also show the strongest correlation with the clinicopathological biomarkers among all cell type specific modules. Conclusion Further analysis indicated that the overall increased expression of the core microglia modules can be well explained by the increased microglia cell population in AD brains instead of bona fide microglia genes’ upregulation. In contrast, the decreased expression and perturbed co-expression in AD neuron modules are due to both neuron cell loss and expression regulation of neuronal pathways including differentially expressed transcription factors such as BCL6 and STAT3, which previous study was not able to identify from the shadow of the cellular composition change. Similarly, the strong changes in expression and co-expression in the astrocyte modules may be also due to a combinatory effect from astrogliosis and astrocyte gene activation in AD brains. In this work, we demonstrated that the combinatorial analyses not only provide a powerful approach to delineate the origin of transcriptomic changes in bulk tissue data, but also lead to a deeper understanding of genes in AD.

scholarly journals Immune response and endocytosis pathways are associated with the escape of Alzheimer’s Disease

2019 ◽  
Author(s):  
Niccolò Tesi ◽  
Sven J. van der Lee ◽  
Marc Hulsman ◽  
Iris E. Jansen ◽  
Najada Stringa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Genetic Variants ◽  
Genetic Risk ◽  
Molecular Mechanisms ◽  
Risk Scores ◽  
Integrative Framework ◽  
Amyloid Metabolism ◽  
Population Controls

AbstractThe risk to develop and escape Alzheimer’s disease (AD) is influenced by a constellation of genetic variants, each associated with specific molecular pathways. Different pathways may differentially contribute to the modification of the AD-risk. We studied the molecular mechanisms that explain the extreme ends of the cognitive spectrum by comparing pathway-specific polygenic risk scores (pathway-PRS) in individuals with AD and those who escaped AD until old age. We used 29 genetic variants associated with AD to calculate pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in patients with AD (N=1,909), population controls (N=1,654), and cognitively healthy centenarians who escaped AD (N=293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and escaping AD (p<0.05). The pathway that contributed the most to the overall modulation of AD-risk was b-amyloid metabolism (32%), driven mainly by APOE variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (p<0.05), while specifically immune response (p=3.1×10−3) and endocytosis (p=3.8×10−4) associated with escaping AD. These pathways were the main contributors to the overall modulation of genetic risk of AD (41.3% and 21.4%, respectively). Our work suggests that immune response and endocytosis might be involved in general neuro-protective functions, and highlights the need to study these pathways, next to b-amyloid metabolism.

scholarly journals Combinatorial analyses reveal cellular composition changes have different impacts on transcriptomic changes of cell type specific genes in Alzheimer’s Disease

2020 ◽  
Author(s):  
Travis S. Johnson ◽  
Shunian Xiang ◽  
Tianhan Dong ◽  
Zhi Huang ◽  
Michael Cheng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Activation ◽  
Cellular Composition ◽  
Cell Type ◽  
Tissue Samples ◽  
Deconvolution Analysis ◽  
Neuron Loss ◽  
Transcriptomic Changes ◽  
Composition Changes

Abstract Alzheimer’s disease (AD) brains are characterized by progressive neuron loss and gliosis. Previous studies comparing AD versus control using bulk brain tissue samples have not considered cell composition changes in AD brains that can cause transcriptional changes not due to transcriptional regulation.Using five large transcriptomic datasets, we mined conserved gene co-expression network modules, and applied differential expression and differential co-expression analysis on the modules in AD versus control brains. Combined with cell type deconvolution analysis, we addressed the question of whether the module expression changes are due to altered cellular composition or transcriptional regulation. Our findings were validated using four additional datasets.We discovered that the increased expression of microglia modules can be explained by increased microglia population in AD brains rather than gene upregulation. In contrast, the decreased expression and perturbed co-expression in AD neuron modules are due to both neuron loss and regulation of neuronal pathways and several transcriptional factors are identified for such regulation. Similarly, the strong changes in expression and co-expression in astrocyte modules can also be attributed to a combinatory effect from astrogliosis and astrocyte gene activation in AD brains. The astrocyte modules expressions also strongly correlated with the clinicopathological biomarkers.In summary, we demonstrated that combinatorial analysis is a powerful approach to delineate the origin of transcriptomic changes in bulk tissue data, which leads to a deeper understanding of key genes/pathways in AD.

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

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.

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

2019 ◽  
Vol 19 (4) ◽  
pp. 216-223 ◽  
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.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
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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