title: A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25-35.
abstract: By means of i.c.v. administration of preaggregated oligomeric beta-amyloid (Abeta)25-35 peptide it was possible in rats to generate neuropathological signs related to those of early stages of Alzheimer's disease (AD). Abeta25-35-administration induced the deposition of endogenously produced amyloid protein. Furthermore, quantitative immunohistochemistry demonstrated time-related statistically significant increases in amyloid immunoreactivity, tau phosphorylation, microglial activation, and astrocytosis, and stereological investigations demonstrated statistically significant increased neuronal cell death and brain atrophy in response to Abeta25-35. Finally, the Abeta25-35-administration led to a reduced short-term memory as determined by the social recognition test. A synthetic peptide termed FGL derived from the neural cell adhesion molecule (NCAM) was able to prevent or, if already manifest, strongly reduce all investigated signs of Abeta25-35-induced neuropathology and cognitive impairment. The FGL peptide was recently demonstrated to be able to cross the blood-brain-barrier. Accordingly, we found that the beneficial effects of FGL were achieved not only by intracisternal, but also by intranasal and s.c. administration of the peptide. Furthermore, FGL-treatment was shown to inhibit the activity of GSK3beta, a kinase implicated in signaling regulating cell survival, tau phosphorylation and the processing of the amyloid precursor protein (APP). Thus, the peptide induced a statistically significant increase in the fraction of GSK3beta phosphorylated on the Ser9-position, a posttranslational modification known to inhibit the activity of the kinase. Hence, the mode of action of FGL with respect to the preventive and curative effects on Abeta25-35-induced neuropathological manifestations and cognitive impairment involves the modulation of intracellular signal-transduction mediated through GSK3beta.
authors.affiliation: ENKAM Pharmaceuticals A/S, Copenhagen, Denmark. klement@plab.ku.dk
authors.forename: B
authors.initials: B
authors.lastname: Klementiev
authors.forename: T
authors.initials: T
authors.lastname: Novikova
authors.forename: V
authors.initials: V
authors.lastname: Novitskaya
authors.forename: P S
authors.initials: PS
authors.lastname: Walmod
authors.forename: O
authors.initials: O
authors.lastname: Dmytriyeva
authors.forename: B
authors.initials: B
authors.lastname: Pakkenberg
authors.forename: V
authors.initials: V
authors.lastname: Berezin
authors.forename: E
authors.initials: E
authors.lastname: Bock
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D004333:Drug Administration Routes; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D019006:Neural Cell Adhesion Molecules / Q000008:administration & dosage*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009483:Neuropsychological Tests; D010446:Peptide Fragments; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000008:administration & dosage; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; C488618:NCAM protein (681-695), human; D019006:Neural Cell Adhesion Molecules; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D016875:tau Proteins; D012601:Scopolamine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3