Browsing by Subject "Neurofibrillary tangles"

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    Cellular localization of p-tau217 in brain and its association with p-tau217 plasma levels
    (BMC, 2022) Wennström, Malin; Janelidze, Shorena; Nilsson, K. Peter R.; The Netherlands Brain Bank; Serrano, Geidy E.; Beach, Thomas G.; Dage, Jeffrey L.; Hansson, Oskar; Neurology, School of Medicine
    Recent studies highlight phosphorylated tau (p-tau) at threonine tau 217 (p-tau217) as a new promising plasma biomarker for pathological changes implicated in Alzheimer's disease (AD), but the specific brain pathological events related to the alteration in p-tau217 plasma levels are still largely unknown. Using immunostaining techniques of postmortem AD brain tissue, we show that p-tau217 is found in neurofibrillary tangles (NFTs) and neuropil threads that are also positive for p-tau181, 202, 202/205, 231, and 369/404. The p-tau217, but not the other five p-tau variants, was also prominently seen in vesicles structure positive for markers of granulovacuolar degeneration bodies and multi-vesicular bodies. Further, individuals with a high likelihood of AD showed significantly higher p-tau217 area fraction in 4 different brain areas (entorhinal cortex, inferior temporal gyrus, and superior frontal gyrus) compared to those with Primary age related tauopathy or other non-AD tauopathies. The p-tau217 area fraction correlated strongly with total amyloid-beta (Aβ) and NFT brain load when the whole group was analyzed. Finally, the mean p-tau217 area fraction correlated significantly with p-tau217 concentrations in antemortem collected plasma specifically in individuals with amyloid plaques and not in those without amyloid plaques. These studies highlight differences in cellular localization of different p-tau variants and suggest that plasma levels of p-tau217 reflect an accumulation of p-tau217 in presence of Aβ plaque load.
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    Enhanced microglial dynamics in the amyloid plaque microenvironment contributes to cognitive resilience in Alzheimer’s disease
    (Wiley, 2025-01-03) Jury, Nur; Redding, Javier; You, Yanwen; Martinez, Pablo; Karahan, Hande; Juarez, Enrique Chimal; Johnson, Travis S.; Zhang, Jie; Kim, Jungsu; Troncoso, Juan C.; Reeves, Cristian A. Lasagna; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Background: Asymptomatic Alzheimer’s disease (AsymAD) refers to individuals with preserved cognition but identifiable Alzheimer’s disease (AD) brain pathology, including beta‐amyloid (Aβ) deposits, neuritic plaques and neurofibrillary tangles upon autopsy. Unlike AD cases, AsymAD exhibits low neuroinflammation and fewer soluble pathological tau species at synaptic levels. However, the link between these observations and the ability to counteract AD pathology is not fully understood. Evidence from AD mice models suggests that the plaque microenvironment significantly influences Aβ plaque‐associated tau pathogenesis. In this study, we investigated the postmortem brains of a cohort of AsymAD cases to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Method: We conducted a detailed histological and biochemical analysis using postmortem brain samples from age‐matched controls (N = 13), AD (N = 19), and AsymAD subjects (N = 17). In fixed brain tissue, we performed the GeoMx whole spatial transcriptome atlas to compare the gene expression within the Aβ‐plaque microenvironment in AsymAD versus AD cases. To further explore the mechanisms insights of our findings we used human microglial cells. Result: Our findings showed that AsymAD cases exhibit an enrichment of core plaques and decreased filamentous plaque accumulation with increased surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD versus AD brains, and tau seeding activity was comparable to that in healthy brains. To further characterize the plaque niche, we used spatial transcriptomics, finding an increase in components of the actin‐based motility pathways within the microglia surrounding amyloid plaques in AsymAD brains. Ongoing mechanistic experiments in vitro aim to elucidate the role of this pathway in microglial response to Aβ. Conclusion: Our findings indicate that the amyloid‐plaque microenvironment in AsymAD brains is characterized by microglia with highly efficient actin‐based cell motility mechanisms and decreased tau seeding versus that observed in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.
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    Structure of Tau filaments in Prion protein amyloidoses
    (Springer, 2021-08) Hallinan, Grace I.; Hoq, Md Rejaul; Ghosh, Manali; Vago, Frank S.; Fernandez, Anllely; Garringer, Holly J.; Vidal, Ruben; Jiang, Wen; Ghetti, Bernardino; Pathology and Laboratory Medicine, School of Medicine
    In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann-Sträussler-Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.
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    The prevalence of tau‐PET positivity in aging and dementia
    (Wiley, 2025-01-09) Coomans, Emma M.; Groot, Colin; Rowe, Christopher C.; Dore, Vincent; Villemagne, Victor L.; van de Giessen, Elsmarieke; van der Flier, Wiesje M.; Pijnenburg, Yolande A. L.; Visser, Pieter Jelle; den Braber, Anouk; Pontecorvo, Michael; Shcherbinin, Sergey; Kennedy, Ian A.; Jagust, William J.; Baker, Suzanne L.; Harrison, Theresa M.; Gispert, Juan Domingo; Shekari, Mahnaz; Minguillon, Carolina; Smith, Ruben; Mattsson-Carlgren, Niklas; Palmqvist, Sebastian; Strandberg, Olof; Stomrud, Erik; Malpetti, Maura; O'Brien, John T.; Rowe, James B.; Jäger, Elena; Bischof, Gérard N.; Drzezga, Alexander; Garibotto, Valentina; Frisoni, Giovanni; Peretti, Débora Elisa; Schöll, Michael; Skoog, Ingmar; Kern, Silke; Sperling, Reisa A.; Johnson, Keith A.; Risacher, Shannon L.; Saykin, Andrew J.; Carrillo, Maria C.; Dickerson, Brad C.; Apostolova, Liana G.; Barthel, Henryk; Rullmann, Michael; Messerschmidt, Konstantin; Vandenberghe, Rik; Van Laere, Koen; Spruyt, Laure; Franzmeier, Nicolai; Brendel, Matthias; Gnörich, Johannes; Benzinger, Tammie L. S.; Lagarde, Julien; Sarazin, Marie; Bottlaender, Michel; Villeneuve, Sylvia; Poirier, Judes; Seo, Sang Won; Gu, Yuna; Kim, Jun Pyo; Mormino, Elizabeth; Young, Christina B.; Vossler, Hillary; Rosa-Neto, Pedro; Therriault, Joseph; Rahmouni, Nesrine; Coath, William; Cash, David M.; Schott, Jonathan M.; Rabinovici, Gil D.; La Joie, Renaud; Rosen, Howard J.; Johnson, Sterling C.; Christian, Bradley T.; Betthauser, Tobey J.; Hansson, Oskar; Ossenkoppele, Rik; Radiology and Imaging Sciences, School of Medicine
    Background Tau‐PET imaging allows in‐vivo detection of neurofibrillary tangles. One tau‐PET tracer (i.e., [18F]flortaucipir) has received FDA‐approval for clinical use, and multiple other tau‐PET tracers have been implemented into clinical trials for participant selection and/or as a primary or secondary outcome measure. To optimize future use of tau‐PET, it is essential to understand how demographic, clinical and genetic factors affect tau‐PET‐positivity rates. Method This large‐scale multi‐center study includes 9713 participants from 35 cohorts worldwide who underwent tau‐PET with [18F]flortaucipir (n = 6420), [18F]RO948 (n = 1999), [18F]MK6240 (n = 878) or [18F]PI2620 (n = 416) (Table‐1). We analyzed individual‐level tau‐PET SUVR data using a cerebellar reference region that were processed either centrally (n = 3855) or by each cohort (n = 5858). We computed cohort‐specific SUVR thresholds based on the mean + 2 standard deviations in a temporal meta‐region of amyloid‐negative cognitively normal (CN) individuals aged >50. Logistic generalized estimating equations were used to estimate tau‐PET‐positivity probabilities, using an exchangeable correlation structure to account for within‐cohort correlations. Analyses were performed with (interactions between) age, amyloid‐status, and APOE‐e4 carriership as independent variables, stratified for syndrome diagnosis. Result The study included 5962 CN participants (7.5% tau‐PET‐positive), 1683 participants with mild cognitive impairment (MCI, 33.8% tau‐PET‐positive) and 2068 participants with a clinical diagnosis of dementia (62.1% tau‐PET‐positive) (Figure‐1). From age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 1.2% [95% CI: 0.9%‐1.5%] to 3.7% [2.3%‐5.1%] among CN amyloid‐negative participants; and from 16.4% [10.8%‐22.1%] to 20.5% [18.8%‐22.2%] among CN amyloid‐positive participants. Among amyloid‐negative participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 3.5% [1.6%‐5.3%] to 11.8% [7.1%‐16.5%] and from 12.6% [4.5%‐20.7%] to 15.9% [6.7%‐25.1%] respectively. In contrast, among amyloid‐positive participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity decreased from 66.5% [57.0%‐76.0%] to 48.3% [42.9%‐53.8%] and from 92.3% [88.7%‐95.9%] to 73.4% [67.5%‐79.3%] respectively. APOE‐e4 status primarily modulated the association of age with tau‐PET‐positivity estimates among CN and MCI amyloid‐positive participants (Figure‐2). Conclusion This large‐scale multi‐cohort study provides robust prevalence estimates of tau‐PET‐positivity, which can aid the interpretation of tau‐PET in the clinic and inform clinical trial designs.