Memantine improves cognition and reduces Alzheimer's-like neuropathology in transgenic mice.
Memantine is an N-methyl-d-aspartate receptor antagonist that is approved for the treatment of moderate to severe Alzheimer's disease (AD). In this study, three groups of triple-transgenic (3xTg-AD) mice with differing levels of AD-like pathology (6, 9, and 15 months of age) were treated for 3 months with doses of memantine equivalent to those used in humans. After the treatment, memantine-treated mice had restored cognition and significantly reduced the levels of insoluble amyloid-beta (Abeta), Abeta dodecamers (Abeta*56), prefibrillar soluble oligomers, and fibrillar oligomers. The effects on pathology were stronger in older, more impaired animals. Memantine treatment also was associated with a decline in the levels of total tau and hyperphosphorylated tau. Finally, memantine pre-incubation prevented Abeta-induced inhibition of long-term potentiation in hippocampal slices of cognitively normal mice. These results suggest that the effects of memantine treatment on AD brain include disease modification and prevention of synaptic dysfunction.
Martinez-Coria
Hilda
H
Department of Neurobiology and Behavior, University of California, Irvine, 3400A Biological Sciences III, Irvine, CA 92697-4545, USA.
Green
Kim N
KN
Billings
Lauren M
LM
Kitazawa
Masashi
M
Albrecht
Miriam
M
Rammes
Gerhard
G
Parsons
Chris G
CG
Gupta
Sandeep
S
Banerjee
Pradeep
P
LaFerla
Frank M
FM
D000367:Age Factors; D000375:Aging / Q000187:drug effects / Q000502:physiology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D008297:Male; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D055503:Protein Multimerization / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000978:Antiparkinson Agents; D016875:tau Proteins; D011494:Protein Kinases; D008559:Memantine