Xiaohuan Gu1,2 · Shan Ping Yu1,2  · Michael Q. Jiang1,2 · Weiwei Zhong1  · Ananth Sastry1  · Ling Wei1

1 Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA 

2 Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA 30033, USA

Abstract

Neuronal and NMDA receptor (NMDAR) hyperactivities are common pathophysiology in Alzheimer’s disease (AD). We recently identified that the deficiency of NMDAR regulatory subunit GluN3A (NR3A) cultivated early psychological and olfactory symptoms, followed by cognitive decline and deferred endogenous amyloid/tau pathologies. NMDAR antagonist memantine (MEM) prevented AD-like progression in GluN3A knockout (KO) mice. We tested the hypothesis that AD development of the 5xFAD mouse can be antagonized by the preemptive MEM treatment. MEM (10 or 20 mg/kg per day in drinking water for 3 months) was started in wild-type (WT) and 5xFAD mice at 3 months old. In this preclinical stage, the 5xFAD mouse displayed psychological and olfactory symptoms, yet exhibited no significant cognitive deficits or Aβ42 deposition. The MEM treatment antagonized early symptoms, abated cognitive decline, and amyloid/tau pathology. Early and persistent maintenance of normal neuronal/NMDAR activities in individuals carrying AD risk factors should be considered as a preventive and a possible disease-modifying therapy.

Keywords

Alzheimer’s disease; 5xFAD mouse; NMDA receptor; Amyloid plaque-independent; Memantine; Disease-modifying therapy; Sporadic and familial AD

[SpringerLink]