Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration

Ishida, Kazuhisa; Yamada, Kaoru; Nishiyama, Risa; Hashimoto, Tadafumi; Nishida, Itaru; Abe, Yoichiro; Yasui, Masato; Iwatsubo, Takeshi

doi:10.1084/jem.20211275

Cited by 110 publications

(85 citation statements)

References 41 publications

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“…The link between tau and AQP4 has been recently shown in two other tau mouse models. Our observed patterns of peri-plaque AQP4 enrichment in arcAβ mice were in agreement with previous reports in tg-ArcSwe mice [24, 79, 80], 5×FAD [74, 81, 82], and APP/PS1 [77, 83–87] mouse models. Behavioral and electrophysiological evidence indicated a neuroprotective role of AQP4 in 5×FAD mice [81].…”

Section: Discussionsupporting

confidence: 93%

“…Upregulated AQP4 mRNA expression, immunofluorescence, and AQP4 depolarization were detected in the caudal cortex of rTg4510 mice [52]. The glymphatic system clears extracellular tau and protects against tau aggregation and neurodegeneration in PS19×AQP4 knockout mice [77]. In addition, altered neurons facing astrocytic AQP4 expression and glymphatic drainage of abnormal tau were found in IL33-deficient mice [78].…”

Section: Discussionmentioning

confidence: 99%

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Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta

Kecheliev

Boss

Maheshwari

et al. 2022

Preprint

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Neurovascular-glymphatic dysfunction plays an important role in Alzheimer’s disease and has been analyzed mainly in association with amyloid-beta (Aβ) pathology. The neurovascular-glymphatic link with tauopathies has not been well elucidated. Here, we aimed to investigate the alterations in the neurovasculature and map the aquaporin 4 (AQP4) distribution and depolarization associated with tau and Aβ. Perfusion, susceptibility weighted imaging and structural magnetic resonance imaging (MRI) were performed in the pR5 P301L mouse model of 4-repeat tau and the arcAβ mouse model of amyloidosis. Immunofluorescence staining was performed using antibodies against AQP4, CD31, astroglia (GFAP, s100β), phospho-tau (AT-8) and Aβ (6E10) in brain tissue slices from P301L, arcAβ and nontransgenic mice. P301L mice showed regional atrophy, preserved cerebral blood flow and reduced cerebral vessel density compared to nontransgenic mice, while arcAβ mice showed cerebral microbleeds and reduced cerebral vessel density. AQP4 depolarization and peri-tau enrichment in the hippocampus and increased AQP4 levels in the forebrain and hippocampus were detected in P301L mice compared to nontransgenic mice. In comparison, cortical AQP4 depolarization and cortical/hippocampal peri-plaque increases were observed in arcAβ mice. Increased s100β-GFAP fluorescence intensities indicative of reactive astrocytes were detected surrounding tau inclusions in P301L mice and Aβ plaques in arcAβ mice. In conclusion, we observed a divergent region-specific AQP4 increase and association with phospho-tau and Aβ pathologies.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta

Kecheliev

Boss

Maheshwari

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Numerous studies have shown that AQP/GFAP expression and AQP4 polarization are critical for the function of the GS (5,24,33). In our study, cortical sites, including the ventral, dorsal, and bilateral cortices, showed consistent trends.…”

Section: Discussionsupporting

confidence: 77%

“…Studies have shown that, after GS function is impaired, excretion insufficiency can lead to abnormal accumulation of metabolic waste, such as tau protein. This outcome has been verified in cerebral hemorrhage, TBI, AD, and other diseases (33,34). In this experiment, SAH reduced the GS function of mice.…”

Section: Discussionsupporting

confidence: 63%

Dynamic Evolution of the Glymphatic System at the Early Stages of Subarachnoid Hemorrhage

Hou

Wang

et al. 2022

Front. Neurol.

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The early stages of subarachnoid hemorrhage (SAH) are extremely important for the progression and prognosis of this disease. The glymphatic system (GS) has positive implications for the nervous system due to its ability to clearance tau and amyloid-β (Aβ) protein. Previous studies have shown that GS dysfunction will appear after SAH. However, there is no systematic evaluation of the degree of damage and development process of GS function in the early stage after SAH. In this study, we evaluated the GS function and neurobehavioral in the sham, 6 h, 1, 3, and 7 days after SAH, respectively. Our results showed that the function of GS was severely attenuated in mice after SAH with a decreased polarity of Aquaporin-4 (AQP4), increased expression of AQP4, a linear correlation with the dystrophin-associated complex (DAC), the proliferation of reactive astrocytes, increased tau protein accumulation, and decreased neurological function. Collectively, these findings provide a comprehensive understanding of the functional changes of GS after SAH, provide references for subsequent scholars studying SAH, and suggest some potential mechanistic insight that affects AQP4 polarity and GS function.

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“…The diurnal rhythm regulates clearing tau from the extracellular space and cerebrospinal fluid [ 15 ]. This may occur through modulation of the lymphatic system, the primary mechanism to clear extracellular solutes that is active during sleep [ 16 , 17 ]. However, the clear evidence linking tau pathology and diurnal dysregulation demonstrated in tau mice and AD patients cannot be fully explained by the impact of circadian abnormality on the glymphatic system.…”

Section: Introductionmentioning

confidence: 99%

The Change in Circadian Rhythms in P301S Transgenic Mice is Linked to Variability in Hsp70-related Tau Disaggregation

et al. 2022

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Circadian disruption often involves a neurodegenerative disorder, such as Alzheimer' s disease or frontotemporal dementia, which are characterized by intraneuronal tau accumulations. The altered sleep pattern and diurnal rhythms in these disorders are the results of tau pathology. The circadian disturbance in reverse is thought to develop and potentially aggravate the condition. However, the underlying mechanism is not fully understood. In this study, perturbed oscillations in BMAL1, the core clock gene, were observed in P301S tau transgenic mice. Tau fractionation analysis of the hippocampus revealed profound fluctuations in soluble and insoluble tau protein levels that were in opposite directions to each other according to zeitgeber time. Interestingly, a diurnal oscillation was detected in the heat shock 70 kDa protein 1A (Hsp70) chaperone that was in-phase with soluble tau but out-of-phase with insoluble tau. Tau protein levels decreased in the soluble and insoluble fractions when Hsp70 was overexpressed in HEK293T cells. Transfection of the BMAL1 carrying vector was continual with the increase in Hsp70 expression and diminished tau protein levels, and it was effectively attenuated by the knockdown of Hsp70, suggesting that Bmal1 could modulate tau protein by Hsp70. Our results suggest that altered circadian oscillations affect tau status and solubility by modulating Hsp70 expression in an experimental model of tau pathology. These findings suggest Hsp70 as a possible pathogenic link between circadian disruption and aggravations of tau pathology.

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Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration

Cited by 110 publications

References 41 publications

Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta

Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta

Dynamic Evolution of the Glymphatic System at the Early Stages of Subarachnoid Hemorrhage

The Change in Circadian Rhythms in P301S Transgenic Mice is Linked to Variability in Hsp70-related Tau Disaggregation

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