Amyloid-β25-35 induces impairment of cognitive function and long-term potentiation through phosphorylation of collapsin response mediator protein 2

Alzheimer's disease (AD) is characterized by amyloid-beta (A beta) protein and tau deposition in the brain. Numerous studies have reported a central role of A beta in the development of AD, but the pathogenesis is not well understood. Collapsin response mediator protein 2 (CRMP2), an intracellular protein mediating a repulsive axon guidance molecule, Semaphorin3A, is also accumulated in neurofibrillary tangles in AD brains. To gain insight into the role of CRMP2 phosphorylation in AD pathogenesis, we investigated the effects of A beta neurotoxicity in CRMP2 phosphorylation-deficient knock-in (crmp2(ki/ki)) mice, in which the serine residue at 522 was replaced with alanine. Intracerebroventricular (i.c.v.) injection of A beta(25-35) peptide, a neurotoxic fragment of A beta protein, to wild-type (wt) mice increased hippocampal phosphorylation of CRMP2. Behavioral assessment revealed that i.c.v. injection of A beta(25-35) peptide caused impairment of novel object recognition in wt mice, while the same peptide did not in crmp2(ki/ki) mice. In electrophysiological recording, wt and crmp2(ki/ki) mice have similar input-output basal synaptic transmission and paired-pulse ratios. However, long-term potentiation was impaired in hippocampal slices of A beta(25-35) peptide-treated wt but not those of crmp2(ki/ki). Our findings indicate that CRMP2 phosphorylation is required for A beta-induced impairment of cognitive memory and synaptic plasticity. (C) 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.