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bioRxiv · 10.1101/2022.04.26.489273

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

Kecheliev, V.·Boss, L.·Maheshwari, U.·Konietzko, U.·Keller, A.·Razansky, D.·Nitsch, R. M.·Klohs, J.·Ni, R.
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Abstract

Neurovascular-glymphatic dysfunction plays an important role in Alzheimers disease and has been analyzed mainly in association with amyloid-beta (A{beta}) 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 A{beta}. Perfusion, susceptibility weighted imaging and structural magnetic resonance imaging (MRI) were performed in the pR5 P301L mouse model of 4-repeat tau and the arcA{beta} mouse model of amyloidosis. Immunofluorescence staining was performed using antibodies against AQP4, CD31, astroglia (GFAP, s100{beta}), phospho-tau (AT-8) and A{beta} (6E10) in brain tissue slices from P301L, arcA{beta} and nontransgenic mice. P301L mice showed regional atrophy, preserved cerebral blood flow and reduced cerebral vessel density compared to nontransgenic mice, while arcA{beta} 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 arcA{beta} mice. Increased s100{beta}-GFAP fluorescence intensities indicative of reactive astrocytes were detected surrounding tau inclusions in P301L mice and A{beta} plaques in arcA{beta} mice. In conclusion, we observed a divergent region-specific AQP4 increase and association with phospho-tau and A{beta} pathologies.

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Kecheliev, V., Boss, L., Maheshwari, U., Konietzko, U., Keller, A., Razansky, D., Nitsch, R. M., Klohs, J., Ni, R.. 2022-04-27. Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta. https://doi.org/10.1101/2022.04.26.489273

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