BDNF-trkB signaling in late life cognitive decline and Alzheimer’s disease

2011 ◽  
Vol 2 (2) ◽  
Author(s):  
Hoau-Yan Wang ◽  
Andres Stucky ◽  
Chang-Gyu Hahn ◽  
Robert Wilson ◽  
David Bennett ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Signaling Pathway ◽  
Neurofibrillary Tangle ◽  
Anterior Cingulate ◽  
Postmortem Brain ◽  
Downstream Signaling ◽  
Postmortem Brain Tissue ◽  
Neurotrophin Signaling ◽  
Neurodegenerative Dementias ◽  
Stimulation Paradigm

AbstractExpression levels of BDNF and trkB, primary components of an important neurotrophin signaling pathway, have been reported to be abnormal in neurodegenerative dementias. Here, we used a novel postmortem brain tissue stimulation paradigm to examine BDNF-induced trkB signaling in participants of the Religious Orders Study, a large longitudinal clinicopathological study of aging and cognition. Thawed slices of anterior cingulate cortex were incubated in BDNF and changes in phosphorylated trkB and downstream signaling molecules ERK2 and Akt were measured, as well as the association of NMDA receptors with trkB. We found that stimulation with BDNF induced much greater activity of the BDNF-trkB signaling pathway in brain tissues of people with cognitive decline and AD, as evidenced by significantly more phosphorylation of trkB (pY-trkB), ERK2 (pY/pT-ERK2), Akt (pS-Akt), and greater BDNF-induced coupling of trKB with NMDAR2A/B. These findings were independent of PHFtau neurofibrillary tangle and amyloid-b plaque densities and other potentially confounding variables. Regression analyses with clinical features further characterized significant relationships between measures of BDNF-trkB activation and domains of cognition and emotional functioning. Increased BDNF-trkB signaling with cognitive decline could reflect a primary derangement of pathway functioning or a compensatory neuroplastic response to counteract neural injury associated with neurodegenerative processes.

scholarly journals Utility of FDG-PET in diagnosis of Alzheimer-related TDP-43 proteinopathy

Neurology ◽  
2020 ◽  
Vol 95 (1) ◽  
pp. e23-e34
Author(s):  
Marina Buciuc ◽  
Hugo Botha ◽  
Melissa E. Murray ◽  
Christopher G. Schwarz ◽  
Matthew L. Senjem ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Fdg Pet ◽  
Hippocampal Sclerosis ◽  
Neurofibrillary Tangle ◽  
Statistical Parametric Mapping ◽  
Postmortem Brain ◽  
Neuritic Plaque ◽  
Cross Sectional ◽  
Postmortem Brain Tissue

ObjectiveTo evaluate FDG-PET as an antemortem diagnostic tool for Alzheimer-related TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy.MethodsWe conducted a cross-sectional neuroimaging–histologic analysis of patients with antemortem FDG-PET and postmortem brain tissue from the Mayo Clinic Alzheimer's Disease Research Center and Study of Aging with Alzheimer spectrum pathology. TDP-43-positive status was assigned when TDP-43-immunoreactive inclusions were identified in the amygdala. Statistical parametric mapping (SPM) analyses compared TDP-43-positive (TDP-43[+]) with TDP-43-negative cases (TDP-43[−]), correcting for field strength, sex, Braak neurofibrillary tangle, and neuritic plaque stages. Cross-validated logistic regression analyses were used to determine whether regional FDG-PET values predict TDP-43 status. We also assessed the ratio of inferior temporal to medial temporal (IMT) metabolism as this was proposed as a biomarker of hippocampal sclerosis.ResultsOf 73 cases, 27 (37%) were TDP-43(+), of which 6 (8%) had hippocampal sclerosis. SPM analysis showed TDP-43(+) cases having greater hypometabolism of medial temporal, frontal superior medial, and frontal supraorbital (FSO) regions (punc < 0.001). Logistic regression analysis showed only FSO and IMT to be associated with TDP-43(+) status, identifying up to 81% of TDP-43(+) cases (p < 0.001). An IMT/FSO ratio was superior to the IMT in discriminating TDP-43(+) cases: 78% vs 48%, respectively.ConclusionsAlzheimer-related TDP-43 proteinopathy is associated with hypometabolism in the medial temporal and frontal regions. Combining FDG-PET measures from these regions may be useful for antemortem prediction of Alzheimer-related TDP-43 proteinopathy.Classification of evidenceThis study provides Class II evidence that hypometabolism in the medial temporal and frontal regions on FDG-PET is associated with Alzheimer-related TDP-43 proteinopathy.

scholarly journals Cellular abnormalities in depression: evidence from postmortem brain tissue

2004 ◽  
Vol 6 (2) ◽  
pp. 185-197
Keyword(s):  
Brain Tissue ◽  
Basic Research ◽  
Brain Regions ◽  
Microscopic Level ◽  
Anterior Cingulate ◽  
Postmortem Brain ◽  
Cell Counting ◽  
The Past ◽  
Postmortem Brain Tissue

During the past two decades, in vivo neuroimaging studies have permitted significant insights into the general location of dysfunctional brain regions in depression. In parallel and often intersecting ways, neuroanatomical, pharmacological, and biochemical studies of postmortem brain tissue are permitting new insights into the pathophysiology of depression. In addition to long-recognized neurochemical abnormalities in depression, novel studies at the microscopic level support the contention that mood disorders are associated with abnormalities in cell morphology and distribution. In the past 6 years, cell-counting studies have identified changes in the density and size of both neurons and glia in a number of frontolimbic brain regions, including dorsolateral prefrontal, orbitofrontal, and anterior cingulate cortex, and the amygdala and hippocampus. Convergence of cellular changes at the microscopic level with neuroimaging changes detected in vivo provides a compelling integration of clinical and basic research for disentangling the pathophysiology of depression. The ultimate integration of these two research approaches will occur with premortem longitudinal clinical studies on well-characterized patients linked to postmortem studies of the same subjects.

scholarly journals In Vivo Detection of Cerebral Cortical Microinfarcts with High-Resolution 7T MRI

2012 ◽  
Vol 33 (3) ◽  
pp. 322-329 ◽  
Author(s):  
Susanne J van Veluw ◽  
Jaco JM Zwanenburg ◽  
JooYeon Engelen-Lee ◽  
Wim GM Spliet ◽  
Jeroen Hendrikse ◽  
...  
Keyword(s):  
High Resolution ◽  
Cognitive Decline ◽  
Ex Vivo ◽  
Brain Slices ◽  
Postmortem Brain ◽  
Vascular Pathology ◽  
Elderly Subjects ◽  
Postmortem Brain Tissue ◽  
Fluid Attenuated Inversion Recovery

Cerebrovascular disease has an important role in cognitive decline and dementia. In this context, cerebral microinfarcts are attracting increasing attention, but these lesions could thus far not be detected in vivo. The aim of this study was to try to identify possible cortical microinfarcts on high-resolution 7T in vivo magnetic resonance imaging (MRI) and to perform a histopathologic validation study on similar appearing lesions on 7T ex vivo MRI of postmortem brain tissue. The study population consisted of 22 elderly subjects, who underwent 7T MRI. The fluid attenuated inversion recovery, T2, and T1 weighted scans of these subjects were examined for possible cortical microinfarcts. In the ex vivo MRI study, 15 formalin-fixed coronal brain slices of 6 subjects with Alzheimer and vascular pathology were examined and subjected to histopathologic verification. On the in vivo scans, 15 cortical lesions could be identified that were likely to be microinfarcts in 6 subjects. In the postmortem tissue, 6 similar appearing lesions were identified of which 5 were verified as cortical microinfarcts on histopathology. This study provides strong evidence that cortical microinfarcts can be detected in vivo, which will be of great value in further studies into the role of vascular disease in cognitive decline and dementia.

scholarly journals Tau protein aggregation induces cellular senescence in the brain

2018 ◽  
Author(s):  
Nicolas Musi ◽  
Joseph M. Valentine ◽  
Kathryn R. Sickora ◽  
Eric Baeuerle ◽  
Cody S. Thompson ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Tau Protein ◽  
Expression Patterns ◽  
Neurofibrillary Tangle ◽  
Postmortem Brain ◽  
Brain Diseases ◽  
Surrounding Tissue ◽  
Protein Accumulation ◽  
Postmortem Brain Tissue ◽  
The Brain

Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI) and over twenty others1. Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss, yet the mechanisms mediating tau toxicity are poorly understood. NFT-containing neurons do not die, which suggests secondary mechanisms are driving toxicity2. We evaluated gene expression patterns of NFT-containing neurons microdissected from AD patient brains3 and found they develop an expression profile consistent with cellular senescence described in dividing cells. This complex stress response induces a near permanent cell cycle arrest, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction4. Moreover, senescent cells induce chronic degeneration of surrounding tissue through the secretion of pro-inflammatory, pro-apoptotic molecules termed the senescence-associated secretory phenotype (SASP)5. Using transgenic mouse models of tau-associated pathogenesis we found that NFTs induced a senescence-like phenotype including DNA damage, karyomegaly, mitochondrial dysfunction and SASP. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT load. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, senolytic treatment reduced total NFT burden, neuron loss and ventricular enlargement; and normalized cerebral blood flow to that of non-transgenic control mice. Collectively, these findings indicate that NFTs induce cellular senescence in the brain, which contributes to neurodegeneration and brain dysfunction. Moreover, given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.

scholarly journals APOE and MAPT Are Associated With Dementia in Neuropathologically Confirmed Parkinson's Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Jon-Anders Tunold ◽  
Hanneke Geut ◽  
J. M. Annemieke Rozemuller ◽  
Sandra Pilar Henriksen ◽  
Mathias Toft ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
Proportional Hazards ◽  
Age At Onset ◽  
Cox Proportional Hazards ◽  
Postmortem Brain ◽  
Tissue Samples ◽  
Postmortem Brain Tissue ◽  
Ε4 Allele

Introduction: Cognitive decline and dementia are common and debilitating non-motor phenotypic features of Parkinson's disease with a variable severity and time of onset. Common genetic variation of the Apolipoprotein E (APOE) and micro-tubule associated protein tau (MAPT) loci have been linked to cognitive decline and dementia in Parkinson's disease, although studies have yielded mixed results. To further elucidate the influence of APOE and MAPT variability on dementia in Parkinson's disease, we genotyped postmortem brain tissue samples of clinically and pathologically well-characterized Parkinson's donors and performed a survival analysis of time to dementia.Methods: We included a total of 152 neuropathologically confirmed Parkinson's disease donors with or without clinical dementia during life. We genotyped known risk variants tagging the APOE ε4 allele and MAPT H1/H2 inversion haplotype. Cox proportional hazards regression analyses adjusted for age at onset, sex and genetic principal components were performed to assess the association between the genetic variants and time from motor onset to onset of dementia.Results: We found that both the APOE ε4 allele (HR 1.82, 95 % CI 1.16–2.83, p = 0.009) and MAPT H1-haplotype (HR 1.71, 95 % CI 1.06–2.78, p = 0.03) were associated with earlier development of dementia in patients with Parkinson's disease.Conclusion: Our results provide further support for the importance of APOE ε4 and MAPT H1-haplotype in the etiology of Parkinson's disease dementia, with potential future relevance for risk stratification and patient selection for clinical trials of therapies targeting cognitive decline in Parkinson's disease.

scholarly journals Single-Cell RNA Sequencing in Parkinson’s Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 368
Author(s):  
Shi-Xun Ma ◽  
Su Bin Lim
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Single Cell ◽  
Rna Sequencing ◽  
Rna Degradation ◽  
Postmortem Brain ◽  
Cell Type ◽  
New Findings ◽  
Postmortem Brain Tissue ◽  
Technical Challenges

Single-cell and single-nucleus RNA sequencing (sc/snRNA-seq) technologies have enhanced the understanding of the molecular pathogenesis of neurodegenerative disorders, including Parkinson’s disease (PD). Nonetheless, their application in PD has been limited due mainly to the technical challenges resulting from the scarcity of postmortem brain tissue and low quality associated with RNA degradation. Despite such challenges, recent advances in animals and human in vitro models that recapitulate features of PD along with sequencing assays have fueled studies aiming to obtain an unbiased and global view of cellular composition and phenotype of PD at the single-cell resolution. Here, we reviewed recent sc/snRNA-seq efforts that have successfully characterized diverse cell-type populations and identified cell type-specific disease associations in PD. We also examined how these studies have employed computational and analytical tools to analyze and interpret the rich information derived from sc/snRNA-seq. Finally, we highlighted important limitations and emerging technologies for addressing key technical challenges currently limiting the integration of new findings into clinical practice.

scholarly journals Identification of upregulated NF-κB inhibitor alpha and IRAK3 targeting lncRNA following intracranial aneurysm rupture-induced subarachnoid hemorrhage

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Leng ◽  
Dan Fan ◽  
Zhong Ren ◽  
Qiaoying Li
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Intracranial Aneurysm ◽  
Signaling Pathway ◽  
Aneurysm Rupture ◽  
Cytokine Receptor ◽  
Gene Set Enrichment Analysis ◽  
Receptor Interaction ◽  
Regulatory Pathways ◽  
Ruptured Intracranial Aneurysm ◽  
Neurotrophin Signaling

Abstract Background This study was performed to identify genes and lncRNAs involved in the pathogenesis of subarachnoid hemorrhage (SAH) from ruptured intracranial aneurysm (RIA). Methods Microarray GSE36791 was downloaded from Gene Expression Omnibus (GEO) database followed by the identification of significantly different expressed RNAs (DERs, including lncRNA and mRNA) between patients with SAH and healthy individuals. Then, the functional analyses of DEmRNAs were conducted and weighted gene co-expression network analysis (WGCNA) was also performed to extract the modules associated with SAH. Following, the lncRNA-mRNA co-expression network was constructed and the gene set enrichment analysis (GSEA) was performed to screen key RNA biomarkers involved in the pathogenesis of SAH from RIA. We also verified the results in a bigger dataset GSE7337. Results Totally, 561 DERs, including 25 DElncRNAs and 536 DEmRNAs, were identified. Functional analysis revealed that the DEmRNAs were mainly associated with immune response-associated GO-BP terms and KEGG pathways. Moreover, there were 6 modules significantly positive-correlated with SAH. The lncRNA-mRNA co-expression network contained 2 lncRNAs (LINC00265 and LINC00937) and 169 mRNAs. The GSEA analysis showed that these two lncRNAs were associated with three pathways (cytokine-cytokine receptor interaction, neurotrophin signaling pathway, and apoptosis). Additionally, IRAK3 and NFKBIA involved in the neurotrophin signaling pathway and apoptosis while IL1R2, IL18RAP and IL18R1 was associated with cytokine-cytokine receptor interaction pathway. The expression levels of these genes have the same trend in GSE36791 and GSE7337. Conclusion LINC00265 and LINC00937 may be implicated with the pathogenesis of SAH from RIA. They were involved in three important regulatory pathways. 5 mRNAs played important roles in the three pathways.

scholarly journals A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu Zhang ◽  
Christopher D. Kontos ◽  
Brian H. Annex ◽  
Aleksander S. Popel
Keyword(s):  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Reaction Network ◽  
Vascular Growth ◽  
Downstream Signaling ◽  
Signaling Axis ◽  
Agonistic Activity ◽  
Molecular Regulatory Mechanisms

AbstractThe Ang–Tie signaling pathway is an important vascular signaling pathway regulating vascular growth and stability. Dysregulation in the pathway is associated with vascular dysfunction and numerous diseases that involve abnormal vascular permeability and endothelial cell inflammation. The understanding of the molecular mechanisms of the Ang–Tie pathway has been limited due to the complex reaction network formed by the ligands, receptors, and molecular regulatory mechanisms. In this study, we developed a mechanistic computational model of the Ang–Tie signaling pathway validated against experimental data. The model captures and reproduces the experimentally observed junctional localization and downstream signaling of the Ang–Tie signaling axis, as well as the time-dependent role of receptor Tie1. The model predicts that Tie1 modulates Tie2’s response to the context-dependent agonist Ang2 by junctional interactions. Furthermore, modulation of Tie1’s junctional localization, inhibition of Tie2 extracellular domain cleavage, and inhibition of VE-PTP are identified as potential molecular strategies for potentiating Ang2’s agonistic activity and rescuing Tie2 signaling in inflammatory endothelial cells.

scholarly journals Protein farnesylation is upregulated in Alzheimer’s human brains and neuron-specific suppression of farnesyltransferase mitigates pathogenic processes in Alzheimer’s model mice

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Angela Jeong ◽  
Shaowu Cheng ◽  
Rui Zhong ◽  
David A. Bennett ◽  
Martin O. Bergö ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Small Gtpases ◽  
Specific Role ◽  
Postmortem Brain ◽  
Effective Prevention ◽  
Postmortem Brain Tissue ◽  
Mtorc1 Signaling ◽  
Behavioral Assessments ◽  
Human Brains

AbstractThe pathogenic mechanisms underlying the development of Alzheimer’s disease (AD) remain elusive and to date there are no effective prevention or treatment for AD. Farnesyltransferase (FT) catalyzes a key posttranslational modification process called farnesylation, in which the isoprenoid farnesyl pyrophosphate is attached to target proteins, facilitating their membrane localization and their interactions with downstream effectors. Farnesylated proteins, including the Ras superfamily of small GTPases, are involved in regulating diverse physiological and pathological processes. Emerging evidence suggests that isoprenoids and farnesylated proteins may play an important role in the pathogenesis of AD. However, the dynamics of FT and protein farnesylation in human brains and the specific role of neuronal FT in the pathogenic progression of AD are not known. Here, using postmortem brain tissue from individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), or Alzheimer’s dementia, we found that the levels of FT and membrane-associated H-Ras, an exclusively farnesylated protein, and its downstream effector ERK were markedly increased in AD and MCI compared with NCI. To elucidate the specific role of neuronal FT in AD pathogenesis, we generated the transgenic AD model APP/PS1 mice with forebrain neuron-specific FT knockout, followed by a battery of behavioral assessments, biochemical assays, and unbiased transcriptomic analysis. Our results showed that the neuronal FT deletion mitigates memory impairment and amyloid neuropathology in APP/PS1 mice through suppressing amyloid generation and reversing the pathogenic hyperactivation of mTORC1 signaling. These findings suggest that aberrant upregulation of protein farnesylation is an early driving force in the pathogenic cascade of AD and that targeting FT or its downstream signaling pathways presents a viable therapeutic strategy against AD.

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