Memantine Attenuates Alzheimer's Disease-Like Pathology and Cognitive Impairment.

Xiaochuan Wang,Inge Grundke-Iqbal,Khalid Iqbal,Julie Blanchard,Emmanuel Planel

doi:10.1371/journal.pone.0145441

Abstract

Deficiency of protein phosphatase-2A is a key event in Alzheimer’s disease. An endogenous inhibitor of protein phosphatase-2A, inhibitor-1, I1 PP2A, which inhibits the phosphatase activity by interacting with its catalytic subunit protein phosphatase-2Ac, is known to be upregulated in Alzheimer’s disease brain. In the present study, we overexpressed I1 PP2A by intracerebroventricular injection with adeno-associated virus vector-1-I1 PP2A in Wistar rats. The I1 PP2A rats showed a decrease in brain protein phosphatase-2A activity, abnormal hyperphosphorylation of tau, neurodegeneration, an increase in the level of activated glycogen synthase kinase-3beta, enhanced expression of intraneuronal amyloid-beta and spatial reference memory deficit; littermates treated identically but with vector only, i.e., adeno-associated virus vector-1-enhanced GFP, served as a control. Treatment with memantine, a noncompetitive NMDA receptor antagonist which is an approved drug for treatment of Alzheimer’s disease, rescued protein phosphatase-2A activity by decreasing its demethylation at Leu309 selectively and attenuated Alzheimer’s disease-like pathology and cognitive impairment in adeno-associated virus vector-1-I1 PP2A rats. These findings provide new clues into the possible mechanism of the beneficial therapeutic effect of memantine in Alzheimer’s disease patients.

Highlights

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders in the elderly population, associated with progressive memory loss and cognitive impairment
In order to study the effect of I1PP2A in AD-like pathology we infected the brains of rat pups within 24 hours of birth
Using 5G6, a specific monoclonal antibody against I1PP2A, Western blots results showed that the level of I1PP2A from the site of injection, namely the ventricular area, to the cerebellum, the cerebral cortex and the hippocampus in associated virus vector-1 (AAV1)-I1PP2A rats, was significantly increased when compared with that in AAV1-GFP control rats

Summary

Introduction

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders in the elderly population, associated with progressive memory loss and cognitive impairment (www. nia.nih.gov; www.alz.org). Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders in the elderly population, associated with progressive memory loss and cognitive impairment It is characterized by the presence of two hallmark lesions: extracellular senile plaques and intracellular neurofibrillary tangles. The former consists of β-amyloid [1]. The major protein subunit of PHFs is the microtubule-associated protein tau in an abnormally hyperphosphorylated state [2, 3]. The induction of AD pathology in transgenic animal models induces cognitive impairment, mechanisms of AD involving tau and Aβ pathologies remains to be PLOS ONE | DOI:10.1371/journal.pone.0145441 December 23, 2015

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