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

Abstract

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.

Hippocampal purinergic P2X7 receptor level is increased in Alzheimer’s disease patients, and associated with amyloid and tau pathologies

“…The sections were permeabilized and blocked in 5% normal donkey or goat serum and 1% Triton-PBS for one hour at room temperature with mild shaking. Free-floating mouse brain tissue sections were incubated with primary antibodies against GFAP, Iba1, AT-8, 6E10, CD68, and P2X7R overnight at 4°C with mild shaking ( Supplemental Table 1 ) (31, 32, 69). The next day, the sections were washed with PBS for 2×20 minutes and incubated with a suitable secondary antibody for 2 hours at room temperature.…”

Hippocampal mGluR5 levels are comparable in Alzheimer’s and control brains, and divergently influenced by amyloid and tau in control brain

“…Immunofluorescence staining using antibodies against mGluR5, Aβ1-16 (6E10), P2X7R and phospho-Tau (AT-8) was performed. Paraffin-embedded fixed human brain tissue sections were incubated with primary antibodies overnight at 4°C with mild shaking (29). The detailed data and quantification of the levels of P2X7Rs in hippocampal tissue from NC and AD patients were obtained from our recent study (43).…”

Evaluation of CB2R expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

“…For immunohistochemical analysis, coronal brain sections (40 μm) were cut around Bregma 0- -2 mm and stained with anti-Aβ antibody 6E10, anti-ionized calcium-binding adapter 1 (Iba1) and anti-CD68 for microgliosis, GFAP for astrocytes and anti-CB 2 R antibody as previously described [20] ( Suppl. Table 2 ).…”