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While deletion of AQP4 is shown to reduce amyloid-\u03b2 (A\u03b2) clearance and exacerbate A\u03b2 peptide accumulation in plaques and vessels of Alzheimer\u2019s disease mouse models, the mechanism and clearing pathways involved are debated. Here, we investigated how inhibiting the function of AQP4 in healthy male C57BL\/6\u00a0J mice impacts clearance of A\u03b240, the more soluble A\u03b2 isoform. Using two-photon in vivo imaging and visualizing vessels with Sulfurodamine 101 (SR101), we first showed that A\u03b240 injected as a\u2009\u2264\u20090.5-\u03bcl volume in the cerebral cortex diffused rapidly in parenchyma and accumulated around blood vessels. In animals treated with the AQP4 inhibitor TGN-020, the perivascular A\u03b240 accumulation was significantly (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001) intensified by involving four times more vessels, thus suggesting a generalized clearance defect associated with vessels. Increasing the injecting volume to \u2265\u20090.5\u2009\u2264\u20091\u00a0\u03bcl decreased the difference of A\u03b240-positive vessels observed in non-treated and AQP4 inhibitor-treated animals, although the difference was still significant (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.001), suggesting that larger injection volumes could overwhelm intramural vascular clearance mechanisms. While both small and large vessels accumulated A\u03b240, for the \u2264\u20090.5-\u03bcl volume group, the average diameter of the A\u03b240-positive vessels tended to be larger in control animals compared with TGN-020-treated animals, although the difference was non-significant (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.066). Using histopathology and ultrastructural microscopy, no vascular structural change was observed after a single massive dose of TGN-020. These data suggest that AQP4 deficiency is directly involved in impaired A\u03b2 brain clearance via the peri-\/para-vascular routes, and AQP4-mediated vascular clearance might counteract blood-brain barrier abnormalities and age-related vascular amyloidopathy.\n                  <\/jats:p>","DOI":"10.1007\/s12035-020-02044-8","type":"journal-article","created":{"date-parts":[[2020,8,11]],"date-time":"2020-08-11T16:08:56Z","timestamp":1597162136000},"page":"4720-4734","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Inhibition of Aquaporin 4 Decreases Amyloid A\u03b240 Drainage Around Cerebral Vessels"],"prefix":"10.1007","volume":"57","author":[{"given":"Gabriela-Camelia","family":"Rosu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan","family":"Catalin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tudor Adrian","family":"Balseanu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mogoanta","family":"Laurentiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaritescu","family":"Claudiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"Kumar-Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9192-7319","authenticated-orcid":false,"given":"Pirici","family":"Daniel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,11]]},"reference":[{"issue":"5580","key":"2044_CR1","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1126\/science.1072994","volume":"297","author":"J Hardy","year":"2002","unstructured":"Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer\u2019s disease: progress and problems on the road to therapeutics. 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