N-truncated amyloid-beta oligomers induce learning impairment and neuronal apoptosis.
N-terminal-truncated forms of amyloid-beta (A beta) peptide have been recently suggested to play a pivotal role early in Alzheimer's disease (AD). Among them, A beta 3(pE)-42 peptide, starting with pyroglutamyl at residue Glu-3, is considered as the predominant A beta species in AD plaques and pre-amyloid lesions. Its abundance is reported to be directly proportional to the severity of the clinical phenotype. The present study investigates the effects of soluble oligomeric A beta 3(pE)-42 after intracerebroventricular injection on mice learning ability and the molecular mechanisms of its in vitro neurotoxicity. Mice injected with soluble A beta 3(pE)-42 or A beta(l-42) displayed impaired spatial working memory and delayed memory acquisition in Y-maze and Morris water maze tests, while those injected with soluble A beta(42-1) showed no effect. These cognitive alterations were associated with free radical overproduction in the hippocampus and olfactory bulbs, but not in the cerebral cortex or cerebellum. In vitro, A beta 3(pE)-42 oligomers induced a redox-sensitive neuronal apoptosis involving caspase activation and an arachidonic acid-dependent pro-inflammatory pathway. These data suggest that A beta 3(pE)-42 could mediate the neurodegenerative process and subsequent cognitive alteration occurring in preclinical AD stages.
Youssef
Ihsen
I
Lipidomix, JE 2482, INPL, Laboratoire de Médecine et Thérapeutique Moléculaire, 15 rue du Bois de la Champelle, 54505 Vandoeuvre-lès-Nancy, France.
Florent-Béchard
Sabrina
S
Malaplate-Armand
Catherine
C
Koziel
Violette
V
Bihain
Bernard
B
Olivier
Jean-Luc
JL
Leininger-Muller
Brigitte
B
Kriem
Badreddine
B
Oster
Thierry
T
Pillot
Thierry
T
D016229:Amyloid beta-Peptides / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D010446:Peptide Fragments / Q000008:administration & dosage*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C532271:amyloid beta-protein (3-42), pyroglutamyl(3)-