The reduced clearance of amyloid-β (Aβ) is thought to contribute to the development of the pathology associated with Alzheimer's disease (AD), which is characterized by the deposition of Aβ plaques. Previous studies have shown that Aβ 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 Aβ clearance and promote Aβ plaque formation, the relative impact of the loss or mislocalization of AQP4 on Aβ deposition has never been directly compared. In this study, we evaluated how the deposition of Aβ plaques within the 5XFAD mouse line is impacted by either Aqp4 gene deletion or the loss of AQP4 localization in the α-syntrophin (Snta1) knockout mouse. We observed that both the absence (Aqp4 KO) and mislocalization (Snta1 KO) of AQP4 significantly increases the parenchymal Aβ plaque and microvascular Aβ deposition across the brain, when compared with 5XFAD littermate controls. Further, the mislocalization of AQP4 had a more pronounced impact on Aβ plaque deposition than did global Aqp4 gene deletion, perhaps pointing to a key role that mislocalization of perivascular AQP4 plays in AD pathogenesis.
Keywords: AQP4; Alzheimer's disease; Amyloid β, perivascular; Astrocytes; Glymphatic system; SNTA1; α syntrophin.
Published by Elsevier Inc.