Upregulation of Na/H Exchanger in Astrogliosis and Early Alzheimer's Disease Pathogenesis.

Reactive astrogliosis has been indicated as one of the earliest pathological biomarkers in Alzheimer's Disease (AD) pathology. We previously reported that upregulation of the Na⁺/H⁺ exchanger isoform 1 (NHE1) protein in reactive astrocytes contributes to neuroinflammation and cognitive function deficits in murine models of ischemic stroke and vascular stenosis. In this study, we utilized AD human post-mortem and APP/PS1dE9 (APP) transgenic mouse brain tissues to determine whether NHE1 upregulation in astrocytes is associated with AD pathogenesis. In both AD human and APP mouse brain tissues, a significant elevation of NHE1 protein expression was detected in glial fibrillary acidic protein expressing (GFAP⁺) reactive astrocytes in cortical and hippocampal regions, compared to control groups. Furthermore, increased astrocytic NHE1 protein and GFAP protein were detected in proximity to amyloid-beta (Aβ) plaques in APP mouse brains. We then tested the efficacy of pharmacological NHE1 inhibition using its inhibitor, HOE642, in attenuating pathogenesis in APP mice. Vehicle-treated APP mice (APP.Veh) exhibited hyperactive locomotor behavior at 4-months and 7-months of age, compared to wild-type littermates (WT.Veh). In contrast, APP mice-treated with HOE642 (APP.HOE) displayed significantly lower hyperactive locomotor behavior (p&;lt0.01). Additionally, APP.HOE mice showed decreased density of amyloid fibrils. In summary, we detected NHE1 protein upregulation in reactive astrocytes in both AD human and APP brains. Pharmacological inhibition of NHE1 protein attenuated pathological Aβ plaque density, and hyperactive locomotor behaviors in APP mice, highlighting NHE1 as a possible therapeutic target for AD.