The effect of aquaporin-4 mis-localization on Aβ deposition in mice

The reduced clearance of amyloid-beta (A beta) is thought to contribute to the development of the pathology associated with Alzheimer's disease (AD), which is characterized by the deposition of A beta plaques. Previous studies have shown that A beta is cleared via the glymphatic system, a brain-wide network of perivascular pathways that supports the exchange between cerebrospinal fluid and interstitial fluid within the brain. Such exchange is dependent upon the water channel aquaporin-4 (AQP4), localized at astrocytic endfeet. While prior studies have shown that both the loss and mislocalization of AQP4 slow A beta clearance and promote A beta plaque formation, the relative impact of the loss or mislocalization of AQP4 on A beta deposition has never been directly compared. In this study, we evaluated how the deposition of A beta plaques within the 5XFAD mouse line is impacted by either Aqp4 gene deletion or the loss of AQP4 localization in the alpha-syntrophin (Snta1) knockout mouse. We observed that both the absence (Aqp4 KO) and mislocalization (Snta1 KO) of AQP4 significantly increases the parenchymal A beta plaque and microvascular A beta deposition across the brain, when compared with 5XFAD littermate controls. Further, the mislocalization of AQP4 had a more pronounced impact on A beta plaque deposition than did global Aqp4 gene deletion, perhaps pointing to a key role that mislocalization of perivascular AQP4 plays in AD pathogenesis.