Memantine rescues transient cognitive impairment caused by high-molecular-weight aβ oligomers but not the persistent impairment induced by low-molecular-weight oligomers

Brain accumulation of soluble amyloid-β oligomers (AβOs) has been implicated in synapse failure and cognitive impairment in Alzheimer's disease (AD). However, whether and how oligomers of different sizes induce synapse dysfunction is a matter of controversy. Here, we report that low-molecular-w...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of neuroscience 2013-06, Vol.33 (23), p.9626-9634
Main Authors: Figueiredo, Cláudia P, Clarke, Julia R, Ledo, José Henrique, Ribeiro, Felipe C, Costa, Carine V, Melo, Helen M, Mota-Sales, Axa P, Saraiva, Leonardo M, Klein, William L, Sebollela, Adriano, De Felice, Fernanda G, Ferreira, Sergio T
Format: Article
Language:English
Subjects:
Amyloid beta-Peptides - antagonists & inhibitors
Amyloid beta-Peptides - chemistry
Amyloid beta-Peptides - toxicity
Animals
Cells, Cultured
Cognition Disorders - chemically induced
Cognition Disorders - drug therapy
Cognition Disorders - metabolism
Male
Memantine - pharmacology
Mice
Molecular Weight
Peptide Fragments - antagonists & inhibitors
Peptide Fragments - chemistry
Peptide Fragments - pharmacology
Peptide Fragments - toxicity
Rats
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Brain accumulation of soluble amyloid-β oligomers (AβOs) has been implicated in synapse failure and cognitive impairment in Alzheimer's disease (AD). However, whether and how oligomers of different sizes induce synapse dysfunction is a matter of controversy. Here, we report that low-molecular-weight (LMW) and high-molecular-weight (HMW) Aβ oligomers differentially impact synapses and memory. A single intracerebroventricular injection of LMW AβOs (10 pmol) induced rapid and persistent cognitive impairment in mice. On the other hand, memory deficit induced by HMW AβOs (10 pmol) was found to be reversible. While memory impairment in LMW oligomer-injected mice was associated with decreased hippocampal synaptophysin and GluN2B immunoreactivities, synaptic pathology was not detected in the hippocampi of HMW oligomer-injected mice. On the other hand, HMW oligomers, but not LMW oligomers, induced oxidative stress in hippocampal neurons. Memantine rescued both neuronal oxidative stress and the transient memory impairment caused by HMW oligomers, but did not prevent the persistent cognitive deficit induced by LMW oligomers. Results establish that different Aβ oligomer assemblies act in an orchestrated manner, inducing different pathologies and leading to synapse dysfunction. Furthermore, results suggest a mechanistic explanation for the limited efficacy of memantine in preventing memory loss in AD.
ISSN:1529-2401
0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.0482-13.2013