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

Abstract

Deficiency of protein phosphatase-2A is a key event in Alzheimer's disease. An endogenous inhibitor of protein phosphatase-2A, inhibitor-1, I1PP2A, 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 I1PP2A by intracerebroventricular injection with adeno-associated virus vector-1-I1PP2A in Wistar rats. The I1PP2A 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-I1PP2A rats. These findings provide new clues into the possible mechanism of the beneficial therapeutic effect of memantine in Alzheimer's disease patients.

• Authors: Xiaochuan Wang, Julie Blanchard, Inge Grundke-Iqbal, Khalid Iqbal
• Journal: PloS one (PLoS One) Vol. 10 Issue 12 Pg. e0145441 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26697860 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ANP32A protein, human
• Dopamine Agents
• Intracellular Signaling Peptides and Proteins
• Nuclear Proteins
• RNA-Binding Proteins
• Protein Phosphatase 2
• Memantine

Topics

• Alzheimer Disease (drug therapy, metabolism, pathology)
• Animals
• Behavior, Animal (drug effects)
• Blotting, Western
• Cognition Disorders (drug therapy)
• Dependovirus (genetics)
• Disease Models, Animal
• Dopamine Agents (administration & dosage, pharmacology)
• Fluorescent Antibody Technique
• Humans
• Immunoenzyme Techniques
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Male
• Memantine (administration & dosage, pharmacology)
• Nuclear Proteins
• Protein Phosphatase 2 (antagonists & inhibitors)
• RNA-Binding Proteins
• Rats
• Rats, Wistar