Tau protein aggregation induces cellular senescence in 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.

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

Neurology ◽

10.1212/wnl.0000000000009722 ◽

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.

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Profiles of matrix metalloproteinases and their inhibitors in plasma of patients with dementia

International Psychogeriatrics ◽

10.1017/s1041610207005790 ◽

2008 ◽

Vol 20 (1) ◽

pp. 67-76 ◽

Cited By ~ 35

Author(s):

Stefan Lorenzl ◽

Katharina Büerger ◽

Harald Hampel ◽

M. Flint Beal

Keyword(s):

Matrix Metalloproteinases ◽

Brain Tissue ◽

Dementia With Lewy Bodies ◽

Constitutive Expression ◽

Lewy Bodies ◽

Postmortem Brain ◽

Plasma Samples ◽

Postmortem Brain Tissue ◽

The Brain ◽

Circulating Levels

ABSTRACTBackground: Matrix metalloproteinases (MMPs) are elevated in the brain tissue of patients with dementia and may play a role in the pathophysiology of dementia. MMP-9 and tissue inhibitors of MMPs (TIMPs) are elevated in postmortem brain tissue of patients with Alzheimer's disease (AD). In a previous study we showed that circulating levels of MMP-9 are elevated in AD patients. The aim of the present study was to examine circulating levels of MMP-1, MMP-2, MMP-9, TIMP-1 and TIMP-2 in the plasma of patients with mild cognitive impairment (MCI), AD, vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD), to determine, whether plasma profiles of MMPs and TIMPs differ in various types of dementia.Methods: Gelatinolytic activity (MMP-2 and MMP-9) was measured in all plasma samples by zymography. Levels of MMP-2, MMP-9, MMP-1 as well as TIMP-1 and TIMP-2 were measured by ELISA.Results: We found constitutive expression of MMP-1, -2 and -9 as well as TIMP-1 and -2 in all the samples investigated. As shown previously, MMP-9 was significantly elevated in the plasma of AD patients (p = 0.004) as compared to controls and MCI patients. Plasma levels of TIMP-1 were significantly lower in VD samples as compared to all other groups. Levels of TIMP-2 were significantly lower in patients with FTD as compared to AD, VaD and MCI patients. There were no significant changes of MMP-1 and MMP-2 levels in the samples.Conclusion: These findings suggest that circulating levels of MMP-9, TIMP-1 and TIMP-2 and changes in the MMP/TIMP balance in plasma differ in various types of dementia.

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Targeting cytochrome P450 46A1 and brain cholesterol 24-hydroxylation to treat neurodegenerative diseases

10.37349/ent.2021.00013 ◽

2021 ◽

Author(s):

Irina Pikuleva

Keyword(s):

Cytochrome P450 ◽

Motor Behavior ◽

Cholesterol Biosynthesis ◽

Cholesterol Content ◽

Brain Diseases ◽

Protein Accumulation ◽

Brain Cholesterol ◽

Tightly Coupled ◽

The Brain

The brain cholesterol content is determined by the balance between the pathways of in situ biosynthesis and cholesterol elimination via 24-hydroxylation catalyzed by cytochrome P450 46A1 (CYP46A1). Both pathways are tightly coupled and determine the rate of brain cholesterol turnover. Evidence is accumulating that modulation of CYP46A1 activity by gene therapy or pharmacologic means could be beneficial in the case of neurodegenerative and other brain diseases and affect brain processes other than cholesterol biosynthesis and elimination. This minireview summarizes these other processes, most common of which include abnormal protein accumulation, memory, and cognition, motor behavior, gene transcription, protein phosphorylation as well as autophagy and lysosomal processing. The unifying mechanisms, by which these processes could be affected by CYP46A targeting are also discussed.

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Changes in the Molecular Structure of the Brain in Bipolar Disorder: Findings using Human Postmortem Brain Tissue

The World Journal of Biological Psychiatry ◽

10.3109/15622970209150613 ◽

2002 ◽

Vol 3 (3) ◽

pp. 125-132 ◽

Cited By ~ 9

Author(s):

Brian Dean

Keyword(s):

Molecular Structure ◽

Bipolar Disorder ◽

Brain Tissue ◽

Postmortem Brain ◽

Human Postmortem Brain ◽

Postmortem Brain Tissue ◽

The Brain

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Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells—Implications for Cancer and Neurodegeneration

Life ◽

10.3390/life11020153 ◽

2021 ◽

Vol 11 (2) ◽

pp. 153

Author(s):

Gregory J. Gillispie ◽

Eric Sah ◽

Sudarshan Krishnamurthy ◽

Mohamed Y. Ahmidouch ◽

Bin Zhang ◽

...

Keyword(s):

Stress Response ◽

Neurodegenerative Diseases ◽

Cell Fate ◽

Cellular Senescence ◽

Stress Responses ◽

Cellular Stress ◽

Surrounding Tissue ◽

Brain Cells ◽

Cell Fate Decisions ◽

The Brain

Cellular stress responses influence cell fate decisions. Apoptosis and proliferation represent opposing reactions to cellular stress or damage and may influence distinct health outcomes. Clinical and epidemiological studies consistently report inverse comorbidities between age-associated neurodegenerative diseases and cancer. This review discusses how one particular stress response, cellular senescence, may contribute to this inverse correlation. In mitotically competent cells, senescence is favorable over uncontrolled proliferation, i.e., cancer. However, senescent cells notoriously secrete deleterious molecules that drive disease, dysfunction and degeneration in surrounding tissue. In recent years, senescent cells have emerged as unexpected mediators of neurodegenerative diseases. The present review uses pre-defined criteria to evaluate evidence of cellular senescence in mitotically competent brain cells, highlights the discovery of novel molecular regulators and discusses how this single cell fate decision impacts cancer and degeneration in the brain. We also underscore methodological considerations required to appropriately evaluate the cellular senescence stress response in the brain.

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Agonal factors distort gene-expression patterns in human postmortem brains

10.1101/2020.07.11.198523 ◽

2020 ◽

Author(s):

Jiacheng Dai ◽

Yu Chen ◽

Chao Chen ◽

Chunyu Liu

Keyword(s):

Gene Expression ◽

Expression Patterns ◽

Postmortem Brain ◽

Gene Expression Patterns ◽

Specific Gene ◽

Surrogate Variable Analysis ◽

Network Analyses ◽

Postmortem Brain Tissue ◽

Postmortem Brains ◽

Study Designs

AbstractAgonal factors, the conditions that occur just prior to death, can impact the molecular quality of postmortem brains, influencing gene expression results. Nevertheless, study designs using postmortem brain tissue rarely, if ever, account for these factors, and previous studies had not documented nor adjusted for agonal factors. Our study used gene expression data of 262 samples from ROSMAP with the following terminal states recorded for each donor: surgery, fever, infection, unconsciousness, difficulty breathing, and mechanical ventilation. Performed differential gene expression and weighted gene co-expression network analyses (WGCNA), fever and infection were the primary contributors to brain gene expression changes. Fever and infection also contributed to brain cell-type specific gene expression and cell proportion changes. Furthermore, the gene expression patterns implicated in fever and infection were unique to other agonal factors. We also found that previous studies of gene expression in postmortem brains were confounded by variables of hypoxia or oxygen level pathways. Therefore, correction for agonal factors through probabilistic estimation of expression residuals (PEER) or surrogate variable analysis (SVA) is recommended to control for unknown agonal factors. Our analyses revealed fever and infection contributing to gene expression changes in postmortem brains and emphasized the necessity of study designs that document and account for agonal factors.

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Single-nucleus transcriptome analysis of human brain immune response in patients with severe COVID-19

Genome Medicine ◽

10.1186/s13073-021-00933-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

John F. Fullard ◽

Hao-Chih Lee ◽

Georgios Voloudakis ◽

Shengbao Suo ◽

Behnam Javidfar ◽

...

Keyword(s):

Immune Response ◽

Choroid Plexus ◽

Transcriptome Analysis ◽

Brain Regions ◽

Postmortem Brain ◽

Network Analyses ◽

Postmortem Brain Tissue ◽

Single Nucleus ◽

The Impact ◽

The Brain

Abstract Background Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has been associated with neurological and neuropsychiatric illness in many individuals. We sought to further our understanding of the relationship between brain tropism, neuro-inflammation, and host immune response in acute COVID-19 cases. Methods Three brain regions (dorsolateral prefrontal cortex, medulla oblongata, and choroid plexus) from 5 patients with severe COVID-19 and 4 controls were examined. The presence of the virus was assessed by western blot against viral spike protein, as well as viral transcriptome analysis covering > 99% of SARS-CoV-2 genome and all potential serotypes. Droplet-based single-nucleus RNA sequencing (snRNA-seq) was performed in the same samples to examine the impact of COVID-19 on transcription in individual cells of the brain. Results Quantification of viral spike S1 protein and viral transcripts did not detect SARS-CoV-2 in the postmortem brain tissue. However, analysis of 68,557 single-nucleus transcriptomes from three distinct regions of the brain identified an increased proportion of stromal cells, monocytes, and macrophages in the choroid plexus of COVID-19 patients. Furthermore, differential gene expression, pseudo-temporal trajectory, and gene regulatory network analyses revealed transcriptional changes in the cortical microglia associated with a range of biological processes, including cellular activation, mobility, and phagocytosis. Conclusions Despite the absence of detectable SARS-CoV-2 in the brain at the time of death, the findings suggest significant and persistent neuroinflammation in patients with acute COVID-19.

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

Translational Neuroscience ◽

10.2478/s13380-011-0015-4 ◽

2011 ◽

Vol 2 (2) ◽

Cited By ~ 7

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.

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