Aquaporin dysfunction and impaired brain interstitial fluid clearance in Alzheimer’s disease – an integrative review
Accumulation of amyloid-beta (Aβ) deposits is one of the neuropathological hallmarks of Alzheimer’s disease (AD), the most frequent neurodegenerative disease in all age groups. While decades of research have focused on the production and aggregation of Aβ peptides, mounting evidence implicate impaired brain fluid dynamics and protein waste clearance as critical contributors to AD pathogenesis. The aquaporin family of water channels, particularly aquaporin-4 (AQP4) and AQP1, has emerged as central regulators of brain interstitial fluid (ISF) homeostasis and Aβ clearance. AQP4, expressed at the perivascular endfeet of astrocytes, is the principal water channel driving fluid convection exchange, acting as a brain-wide network in which ISF and solutes are cleared via venous, paravenous and periarterial routes, as well as through dural lymphatic vessels and along perineural spaces. AQP1, expressed predominantly in the choroid plexus epithelium, governs cerebrospinal fluid (CSF) secretion and thereby modulates the pressure gradients that sustain this convective flow. This review provides an integrated overview of the molecular pathology of AD, the physiological roles of AQP4 and AQP1, together with the major anatomical pathways of ISF and CSF drainage from the brain. We next address to the genetic and pharmacological modulation of AQP4 and AQP1 in transgenic AD mouse models and describe the resulting pathological changes. AQP4 knockout consistently exacerbates Aβ pathology and cognitive deficits, with the abnormal distribution of AQP4 within the astrocyte being sufficient to impair clearance, and these data highlight the critical importance of polarized expression versus bulk expression levels. AQP1 modulation, though less studied, alters CSF dynamics and may influence Aβ clearance indirectly through changes in CSF turnover. Pharmacological agents targeting AQP4 and AQP1 offer promising avenues for therapeutic intervention. Understanding the distinct and intersecting roles of aquaporins in brain fluid homeostasis may yield novel strategies for restoring protein clearance in AD.