scholarly journals The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans

Science ◽  
2019 ◽  
Vol 363 (6429) ◽  
pp. 880-884 ◽  
Author(s):  
Jerrah K. Holth ◽  
Sarah K. Fritschi ◽  
Chanung Wang ◽  
Nigel P. Pedersen ◽  
John R. Cirrito ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Sleep Deprivation ◽  
Interstitial Fluid ◽  
Tau Pathology ◽  
Brain Interstitial Fluid ◽  
Spreading Model ◽  
Csf Levels ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Chronic Sleep

The sleep-wake cycle regulates interstitial fluid (ISF) and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ) that accumulates in Alzheimer’s disease (AD). Furthermore, chronic sleep deprivation (SD) increases Aβ plaques. However, tau, not Aβ, accumulation appears to drive AD neurodegeneration. We tested whether ISF/CSF tau and tau seeding and spreading were influenced by the sleep-wake cycle and SD. Mouse ISF tau was increased ~90% during normal wakefulness versus sleep and ~100% during SD. Human CSF tau also increased more than 50% during SD. In a tau seeding-and-spreading model, chronic SD increased tau pathology spreading. Chemogenetically driven wakefulness in mice also significantly increased both ISF Aβ and tau. Thus, the sleep-wake cycle regulates ISF tau, and SD increases ISF and CSF tau as well as tau pathology spreading.

scholarly journals Association of amyloid-β CSF/PET discordance and tau load 5 years later

Neurology ◽  
2020 ◽  
Vol 95 (19) ◽  
pp. e2648-e2657 ◽  
Author(s):  
Juhan Reimand ◽  
Lyduine Collij ◽  
Philip Scheltens ◽  
Femke Bouwman ◽  
Rik Ossenkoppele ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Tau Pathology ◽  
Cognitively Normal ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Tau Pet

ObjectiveTo investigate the association between discordant β-amyloid (Aβ) PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later.MethodsWe included 730 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]florbetapir PET and CSF Aβ42 available. Aβ CSF/PET status was determined at baseline using established cutoffs. Longitudinal data were available for [18F]florbetapir (Aβ) PET (baseline to 4.3 ± 1.9 years), CSF (p)tau (baseline to 2.0 ± 0.1 years), cognition (baseline to 4.3 ± 2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2 ± 1.2 years after baseline to 1.6 ± 0.7 years later). We used linear mixed modeling to study the association between Aβ CSF/PET status and tau pathology measured in CSF or using PET. We calculated the proportion of CSF+/PET− participants who during follow-up (1) progressed to Aβ CSF+/PET+ or (2) became tau-positive based on [18F]flortaucipir PET.ResultsAβ CSF+/PET+ (n = 318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET− (n = 80) participants were overall similar to the CSF−/PET− (N = 306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET− group (1.20 ± 0.13) did not differ from CSF−/PET− (1.18 ± 0.08, p = 0.69), but was substantially lower than CSF+/PET+ (1.48 ± 0.44, p < 0.001). Of the CSF+/PET− participants, 21/64 (33%) progressed to Aβ CSF+/PET+, whereas only one (3%, difference p < 0.05) became tau-positive based on [18F]flortaucipir PET.ConclusionsAβ load detectable by both CSF and PET seems to precede substantial tau deposition. Compared to participants with abnormal Aβ levels on both PET and CSF, the CSF+/PET− group has a distinctly better prognosis.

scholarly journals Tau in the brain interstitial fluid is fragmented and seeding-competent

2020 ◽  
Author(s):  
Erica Barini ◽  
Gudrun Plotzky ◽  
Yulia Mordashova ◽  
Jonas Hoppe ◽  
Esther Rodriguez-Correa ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Interstitial Fluid ◽  
List Type ◽  
Fragmentation Pattern ◽  
Tau Pathology ◽  
Brain Areas ◽  
Brain Interstitial Fluid ◽  
Tau Aggregation ◽  
The Brain

SUMMARYIn Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells and notably, only a small fraction of Tau, separated by ultracentrifugation, is seeding competent. These results indicate that only a subset of Tau accounts for ISF seeding competence and have the potential to contribute to the propagation of Tau pathology.Graphical abstractHighlights✓In transgenic mice, interstitial fluid comprises several Tau fragments spanning the entire Tau sequence.✓Interstitial fluid Tau concentration decreases with Tauopathy progression, while phosphorylation increases.✓Only interstitial fluid from mice with established Tauopathy is seeding competent in vitro.✓Interstitial fluid seeding competence is driven by less soluble, aggregated and phosphorylated Tau species.In BriefBarini et al. show that in the brain interstitial fluid of Tau transgenic mice, truncated Tau decreases, while its phosphorylation increases during the progression of pathology. A subset of less soluble, aggregated and phosphorylated ISF Tau induces Tau aggregation in cells.

scholarly journals The Choroid Plexus Removes β-Amyloid from Brain Cerebrospinal Fluid

2005 ◽  
Vol 230 (10) ◽  
pp. 771-776 ◽  
Author(s):  
Janelle S. Crossgrove ◽  
G. Jane Li ◽  
Wei Zheng
Keyword(s):  
Cerebrospinal Fluid ◽  
Choroid Plexus ◽  
Volume Of Distribution ◽  
Temperature Dependent ◽  
Cellular Accumulation ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Brain ◽  
And Diffusion ◽  
Isolated Rat

β-Amyloid (Aβ) concentration in the cerebrospinal fluid (CSF) of the brain may be regulated by the choroid plexus, which forms a barrier between blood and brain CSF. Aβ uptake from CSF was determined as its volume of distribution (VD) into isolated rat choroid plexus tissue. The VD of [125l]Aβ1–40 was corrected by subtraction of the VD of [14C]sucrose, a marker for extracellular space and diffusion. Aβ uptake into choroid plexus was time and temperature dependent. Uptake of [125l]Aβ was saturable. Aβ uptake was not affected by addition of transthyretin or apolipoprotein E3. In studies with primary culture monolayers of choroidal epithelial cells in Transwells, Aβ permeability across cells, corrected by [14C]sucrose, was greater from the CSF-facing membrane than from the blood-facing membrane. Similarly, cellular accumulation of [125l]Aβ was concentrative from both directions and was greater from the CSF-facing membrane, suggesting a bias for efflux. Overall, these results suggest the choroid plexus selectively cleanses Aβ from the CSF by an undetermined mechanism(s), potentially reducing Aβ from normal brains and the brains of Alzheimer's disease patients.

scholarly journals O-GlcNAcylation ameliorates the pathological manifestations of Alzheimer’s disease by inhibiting necroptosis

2021 ◽  
Vol 7 (3) ◽  
pp. eabd3207
Author(s):  
Jinsu Park ◽  
Hee-Jin Ha ◽  
Eun Seon Chung ◽  
Seung Hyun Baek ◽  
Yoonsuk Cho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuronal Loss ◽  
Protective Role ◽  
Tau Pathology ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
5Xfad Mice ◽  
Ad Mouse Model ◽  
M2 Phenotype

O-GlcNAcylation (O-linked β-N-acetylglucosaminylation) is notably decreased in Alzheimer’s disease (AD) brain. Necroptosis is activated in AD brain and is positively correlated with neuroinflammation and tau pathology. However, the links among altered O-GlcNAcylation, β-amyloid (Aβ) accumulation, and necroptosis are unclear. Here, we found that O-GlcNAcylation plays a protective role in AD by inhibiting necroptosis. Necroptosis was increased in AD patients and AD mouse model compared with controls; however, decreased necroptosis due to O-GlcNAcylation of RIPK3 (receptor-interacting serine/threonine protein kinase 3) was observed in 5xFAD mice with insufficient O-linked β-N-acetylglucosaminase. O-GlcNAcylation of RIPK3 suppresses phosphorylation of RIPK3 and its interaction with RIPK1. Moreover, increased O-GlcNAcylation ameliorated AD pathology, including Aβ burden, neuronal loss, neuroinflammation, and damaged mitochondria and recovered the M2 phenotype and phagocytic activity of microglia. Thus, our data establish the influence of O-GlcNAcylation on Aβ accumulation and neurodegeneration, suggesting O-GlcNAcylation–based treatments as potential interventions for AD.

scholarly journals Effect of 1 Night of Total Sleep Deprivation on Cerebrospinal Fluid β-Amyloid 42 in Healthy Middle-Aged Men

2014 ◽  
Vol 71 (8) ◽  
pp. 971 ◽  
Author(s):  
Sharon Ooms ◽  
Sebastiaan Overeem ◽  
Kees Besse ◽  
Marcel Olde Rikkert ◽  
Marcel Verbeek ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Sleep Deprivation ◽  
Middle Aged ◽  
Total Sleep Deprivation ◽  
Β Amyloid
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