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bioRxiv · 10.1101/2020.01.31.928481

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

Wu, C.·Feng, Y.-w.·Zhang, Q.·Liang, F.-y.·Lan, Y.·Pei, Z.·Xu, G.-q.
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Abstract

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.

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Wu, C., Feng, Y.-w., Zhang, Q., Liang, F.-y., Lan, Y., Pei, Z., Xu, G.-q.. 2020-01-31. Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms. https://doi.org/10.1101/2020.01.31.928481

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