Overexpression of Slit2 improves function of the paravascular pathway in the aging mouse brain

Aging is associated with impairment of the paravascular pathway caused by the activation of astrocytes and depolarization of protein aquaporin-4 (AQP4) water channels, resulting in the accumulation of protein waste, including amyloid β (Aβ), in the brain parenchyma. The secreted glycoprotein slit guidance ligand 2 (Slit2) is important in regulating the function of the central nervous system and inflammatory response process. In the present study, 15-month-old Slit2 overexpression transgenic mice (Slit2-Tg mice) and two-photon fluorescence microscopy were used to evaluate the dynamic clearance of the paravascular pathway and the integrity of the blood-brain barrier (BBB). The reactivity of astrocytes, polarity of AQP4 and deposition of Aβ in the brain parenchyma were analyzed by immunofluorescence. A Morris water maze test was used to examine the effect of Slit2 on spatial memory cognition in aging mice. It was found that the overexpression of Slit2 improved the clearance of the paravascular pathway by inhibiting astrocyte activation and maintaining AQP4 polarity on the astrocytic endfeet in Slit2-Tg mice. In addition, Slit2 restored the disruption of the BBB caused by aging. The accumulation of Aβ was significantly reduced in the brain of Slit2-Tg mice. Furthermore, the water maze experiment showed that Slit2 improved spatial memory cognition in the aging mice. These results indicated that Slit2 may have the potential to be used in the prevention and treatment of neurodegenerative diseases in the elderly.