Dataset Information

Gene Profiling of Nucleus Basalis Tau Containing Neurons in Chronic Traumatic Encephalopathy: A Chronic Effects of Neurotrauma Consortium Study.

ABSTRACT: Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increased number of NFTs across the pathological stages of CTE. However, molecular mechanisms underlying nbM neurodegeneration in the context of CTE pathology remain unknown. Here, we assessed the genetic signature of nbM neurons containing the p-tau pretangle maker pS422 from CTE subjects who came to autopsy and received a neuropathological CTE staging assessment (Stages II, III, and IV) using laser capture microdissection and custom-designed microarray analysis. Quantitative analysis revealed dysregulation of key genes in several gene ontology groups between CTE stages. Specifically, downregulation of the nicotinic cholinergic receptor subunit ?-2 gene (CHRNB2), monoaminergic enzymes catechol-O-methyltransferase (COMT) and dopa decarboxylase (DDC), chloride channels CLCN4 and CLCN5, scaffolding protein caveolin 1 (CAV1), cortical development/cytoskeleton element lissencephaly 1 (LIS1), and intracellular signaling cascade member adenylate cyclase 3 (ADCY3) was observed in pS422-immunreactive nbM neurons in CTE patients. By contrast, upregulation of calpain 2 (CAPN2) and microtubule-associated protein 2 (MAP2) transcript levels was found in Stage IV CTE patients. These single-population data in vulnerable neurons indicate alterations in gene expression associated with neurotransmission, signal transduction, the cytoskeleton, cell survival/death signaling, and microtubule dynamics, suggesting novel molecular pathways to target for drug discovery in CTE.

SUBMITTER: Mufson EJ

PROVIDER: S-EPMC5962931 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

Gene Profiling of Nucleus Basalis Tau Containing Neurons in Chronic Traumatic Encephalopathy: A Chronic Effects of Neurotrauma Consortium Study.

Mufson Elliott J EJ He Bin B Ginsberg Stephen D SD Carper Benjamin A BA Bieler Gayle S GS Crawford Fiona F Alvarez Victor E VE Huber Bertrand R BR Stein Thor D TD McKee Ann C AC Perez Sylvia E SE

Journal of neurotrauma 20180405 11

Military personnel and athletes exposed to traumatic brain injury may develop chronic traumatic encephalopathy (CTE). Brain pathology in CTE includes intracellular accumulation of abnormally phosphorylated tau proteins (p-tau), the main constituent of neurofibrillary tangles (NFTs). Recently, we found that cholinergic basal forebrain (CBF) neurons within the nucleus basalis of Meynert (nbM), which provide the major cholinergic innervation to the cortex, display an increased number of NFTs across ...[more]

PMID: 29338612

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Project description:Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition associated with repetitive traumatic brain injury (rTBI) seen in contact-sport athletes and military personnel. The medial temporal lobe (MTL; i.e., hippocampus, subiculum, and entorhinal and perirhinal cortices) memory circuit displays tau lesions during the pathological progression of CTE. We examined MTL tissue obtained from 40 male Caucasian and African American athletes who received a postmortem CTE neuropathological diagnosis defined as stage II, III, or IV. Sections were immunolabeled using an early (AT8) or a late (TauC3) marker for pathological tau and for amyloid beta (Aβ) species (6E10, Aβ1-42 and thioflavin S). Stereological analysis revealed that stage III had significantly less AT8-positive neurons and dystrophic neurites than stage IV in all MTL regions except hippocampal subfield CA3, whereas significantly more AT8-positive neurons, dystrophic neurites, and neurite clusters were found in the perirhinal cortex, entorhinal cortex, hippocampal CA1, and subiculum of CTE stage III compared with stage II. TauC3-positive pathology was significantly higher in the perirhinal and subicular cortex of stage IV compared to stage III and the perirhinal cortex of stage III compared to stage II. AT8-positive neurite clusters were observed in stages III and IV, but virtually absent in stage II. When observed, Aβ pathology appeared as amyloid precursor protein (APP)/Aβ (6E10)-positive diffuse plaques independent of region. Thioflavine S labeling, did not reveal evidence for fibril or neuritic pathology associated with plaques, confirming a diffuse, non-cored plaque phenotype in CTE. Total number of AT8-positive profiles correlated with age at death, age at symptom onset, and time from retirement to death. There was no association between AT8-positive tau pathology and age sport began, years played, or retirement age, and no difference between CTE stage and the highest level of sport played. In summary, our findings demonstrate different tau profiles in the MTL across CTE stages, proffering CA3 tau pathology and MTL dystrophic neurite clusters as possible markers for the transition between early (II) and late (III/IV) stages, while highlighting CTE as a progressive noncommunicative tauopathy.

Project description:Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy characterized by accumulation of hyperphosphorylated tau (p-tau) in perivascular aggregates in neurons and glia at the depths of neocortical sulci and progresses to diffuse neocortical, allocortical and brainstem structures. The strongest risk factor is exposure to repetitive head impacts acquired most commonly through contact sports and military service. Given that CTE can only be definitively diagnosed after death, a better understanding of the cellular and molecular changes in CTE brains may lead to identification of mechanisms that could be used for novel biomarkers, monitoring progression or therapeutic development. Disruption of alternative pre-mRNA splicing of tau mRNA plays a pathogenic role in tauopathy, with multiple characteristic patterns of isoform accumulation varying among tauopathies. Limited data are available on CTE, particularly at early stages. Using biochemical and histological approaches, we performed a detailed characterization of tau isoform signatures in post-mortem human brain tissue from individuals with a range of CTE stages (n = 99). In immunoblot analyses, severity was associated with decreased total monomeric tau and increased total oligomeric tau. Immunoblot with isoform-specific antisera revealed that oligomeric tau with three and four microtubule binding domain repeats (3R and 4R) also increased with CTE severity. Similarly, immunohistochemical studies revealed p-tau accumulation consisting of both 3R and 4R in perivascular lesions. When the ratio of 4R:3R was analyzed, there was mixed expression throughout CTE stages, although 4R predominated in early CTE stages (I-II), a 3R shift was observed in later stages (III-IV). While neurons were found to contain both 3R and 4R, astrocytes only contained 4R. These 4R-positive cells were exclusively neuronal at early stages. Overall, these findings demonstrate that CTE is a mixed 4R/3R tauopathy. Furthermore, histologic analysis reveals a progressive shift in tau isoforms that correlates with CTE stage and extent of neuronal pathology.

Project description:Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers1-3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4-7. No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies10,11. However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro12-15. Similar to Alzheimer's disease12,14,16-18, all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.

Dataset Information

Gene Profiling of Nucleus Basalis Tau Containing Neurons in Chronic Traumatic Encephalopathy: A Chronic Effects of Neurotrauma Consortium Study.

Publications

Gene Profiling of Nucleus Basalis Tau Containing Neurons in Chronic Traumatic Encephalopathy: A Chronic Effects of Neurotrauma Consortium Study.

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