Inhibition of Aquaporin 4 Decreases Amyloid Aβ40 Drainage Around Cerebral Vessels

Abstract

Aquaporin-4 (AQP4) is located mainly in the astrocytic end-feet around cerebral blood vessels and regulates ion and water homeostasis in the brain. While deletion of AQP4 is shown to reduce amyloid-β (Aβ) clearance and exacerbate Aβ peptide accumulation in plaques and vessels of Alzheimer’s 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 J mice impacts clearance of Aβ40, the more soluble Aβ isoform. Using two-photon in vivo imaging and visualizing vessels with Sulfurodamine 101 (SR101), we first showed that Aβ40 injected as a ≤ 0.5-μl 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 Aβ40 accumulation was significantly (P < 0.001) intensified by involving four times more vessels, thus suggesting a generalized clearance defect associated with vessels. Increasing the injecting volume to ≥ 0.5 ≤ 1 μl decreased the difference of Aβ40-positive vessels observed in non-treated and AQP4 inhibitor-treated animals, although the difference was still significant (P = 0.001), suggesting that larger injection volumes could overwhelm intramural vascular clearance mechanisms. While both small and large vessels accumulated Aβ40, for the ≤ 0.5-μl volume group, the average diameter of the Aβ40-positive vessels tended to be larger in control animals compared with TGN-020-treated animals, although the difference was non-significant (P = 0.066). 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 Aβ brain clearance via the peri-/para-vascular routes, and AQP4-mediated vascular clearance might counteract blood-brain barrier abnormalities and age-related vascular amyloidopathy.

Role of adipocyte Na,K-ATPase oxidant amplification loop in cognitive decline and neurodegeneration

“…Doxycycline induced adipocyte specific NaKtide expression in these WD fed mice significantly attenuated the Iba1-positive microglia in the hippocampus ( Figure S3 ). These findings were consistent with the plasma levels of amyloid beta-40 (Aβ-40), a marker of cognitive decline ( Jakel et al., 2020 ; Rosu et al., 2020 ; Tsai et al., 2021 ; Watt et al., 2020 ), which showed significant increases in the WD fed mice ( Figure 3 F). The increase in Aβ-40 levels was significantly attenuated by doxycycline induced NaKtide expression ( Figure 3 F).…”

Aquaporin-4 and Cognitive Disorders

“…Additionally, AQP4 deficiency downregulates the expression of low-density lipoprotein receptor-related protein-1 (LRP1), which mediates Aβ excretion [ 20 - 23 ]. In a recent study that used two-photon in vivo imaging to visualize vessels using sulforhodamine 101 (SR101), significantly more perivascular Aβ deposition was observed in mice treated with the AQP4 inhibitor TGN-020 than in mice in the control group [ 24 ]. This is direct evidence that the inhibition of AQP4 function can reduce Aβ vascular drainage.…”

Canonical Bone Morphogenetic Protein Signaling Regulates Expression of Aquaporin-4 and Its Anchoring Complex in Mouse Astrocytes

“…Our data point to the possible involvement of BMPs in conditions where a mislocalization of AQP4 is paired with its preserved or enhanced expression. Alzheimer’s Disease (AD) is a notable example: a decade ago it was shown in a mouse model of AD that AQP4 was conspicuously absent from endfeet adjoining amyloid plaques ( Yang et al, 2011 ), while more recent studies have demonstrated reduced amyloid clearance following targeted disruption of Aqp4 ( Iliff et al, 2012 ; Xu et al, 2015 ; Smith et al, 2019 ; Rosu et al, 2020 ). AD is associated with upregulation of BMPs and activation of the Smad1/5/9 pathway ( Li et al, 2008 ; Zhang et al, 2021 ).…”