Neurotoxicity and memory deficits induced by soluble low-molecular-weight amyloid-β1-42 oligomers are revealed in vivo by using a novel animal model.
Neuronal and synaptic degeneration are the best pathological correlates for memory decline in Alzheimer's disease (AD). Although the accumulation of soluble low-molecular-weight amyloid-β (Aβ) oligomers has been suggested to trigger neurodegeneration in AD, animal models overexpressing or infused with Aβ lack neuronal loss at the onset of memory deficits. Using a novel in vivo approach, we found that repeated hippocampal injections of small soluble Aβ(1-42) oligomers in awake, freely moving mice were able to induce marked neuronal loss, tau hyperphosphorylation, and deficits in hippocampus-dependent memory. The neurotoxicity of small Aβ(1-42) species was observed in vivo as well as in vitro in association with increased caspase-3 activity and reduced levels of the NMDA receptor subunit NR2B. We found that the sequestering agent transthyretin is able to bind the toxic Aβ(1-42) species and attenuated the loss of neurons and memory deficits. Our novel mouse model provides evidence that small, soluble Aβ(1-42) oligomers are able to induce extensive neuronal loss in vivo and initiate a cascade of events that mimic the key neuropathological hallmarks of AD.
INSERM, UMR837, Alzheimer and Tauopathies, 59045 Lille, France.
Jonathan
J
Brouillette
Raphaëlle
R
Caillierez
Nadège
N
Zommer
Claire
C
Alves-Pires
Iryna
I
Benilova
David
D
Blum
Bart
B
De Strooper
Luc
L
Buée
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001362:Avoidance Learning; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005561:Formates / Q000494:pharmacology; D006624:Hippocampus; D007150:Immunohistochemistry; D007267:Injections; D007536:Isomerism; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced* / Q000473:pathology / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008970:Molecular Weight; D009474:Neurons / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000523:psychology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D010766:Phosphorylation; D011228:Prealbumin / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D005561:Formates; D010446:Peptide Fragments; D011228:Prealbumin; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C030544:formic acid