Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms

The glymphatic system contributes to a large proportion of brain waste clearance, including removal of amyloid {beta} (A{beta}). We have demonstrated that glutamate and {gamma}-aminobutyric acid (GABA) influence glymphatic clearance through distinct mechanisms whereby GABA exerts modulatory effects in an aquaporin-4 (AQP4)-dependent manner while the actions of glutamate are pulsation-dependent. The efficacy of GABA and glutamate in alleviating A{beta} in APP-PS1 and Angiotensin-II (Ang-II) induced hypertension mouse models was further evaluated. Notably, increasing GABA or inhibiting glutamate levels led to reduced binding of A{beta} to pre-labeled plaques to similar extents in APP-PS1 mice while GABA appeared more efficient in A{beta} clearance in hypertensive animals than the glutamate inhibitor. Our findings support the modulation of neurotransmitters that influence the glymphatic pathway via distinct mechanisms as a potentially effective therapeutic strategy for clearance of A{beta} deposits from the brain.