Amyloid-beta induced CA1 pyramidal cell loss in young adult rats is alleviated by systemic treatment with FGL, a neural cell adhesion molecule-derived mimetic peptide.
Increased levels of neurotoxic amyloid-beta in the brain are a prominent feature of Alzheimer's disease. FG-Loop (FGL), a neural cell adhesion molecule-derived peptide that corresponds to its second fibronectin type III module, has been shown to provide neuroprotection against a range of cellular insults. In the present study impairments in social recognition memory were seen 24 days after a 5 mg/15 µl amyloid-beta(25-35) injection into the right lateral ventricle of the young adult rat brain. This impairment was prevented if the animal was given a systemic treatment of FGL. Unbiased stereology was used to investigate the ability of FGL to alleviate the deleterious effects on CA1 pyramidal cells of the amyloid-beta(25-35) injection. NeuN, a neuronal marker (for nuclear staining) was used to identify pyramidal cells, and immunocytochemistry was also used to identify inactive glycogen synthase kinase 3beta (GSK3β) and to determine the effects of amyloid-beta(25-35) and FGL on the activation state of GSK3β, since active GSK3β has been shown to cause a range of AD pathologies. The cognitive deficits were not due to hippocampal atrophy as volume estimations of the entire hippocampus and its regions showed no significant loss, but amyloid-beta caused a 40% loss of pyramidal cells in the dorsal CA1 which was alleviated partially by FGL. However, FGL treatment without amyloid-beta was also found to cause a 40% decrease in CA1 pyramidal cells. The action of FGL may be due to inactivation of GSK3β, as an increased proportion of CA1 pyramidal neurons contained inactive GSK3β after FGL treatment. These data suggest that FGL, although potentially disruptive in non-pathological conditions, can be neuroprotective in disease-like conditions.
Open University, Department of Life, Health and Chemical Sciences, Milton Keynes, United Kingdom. nicola_j_corbett@rush.edu
Nicola J
NJ
Corbett
Paul L
PL
Gabbott
Boris
B
Klementiev
Heather A
HA
Davies
Frances M
FM
Colyer
Tatiana
T
Novikova
Michael G
MG
Stewart
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D002452:Cell Count; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000494:pharmacology*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000009:adverse effects*; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D034961:Antigens, Nuclear; C488618:NCAM protein (681-695), human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D010446:Peptide Fragments; C546339:Rbfox3 protein, rat; C074636:amyloid beta-protein (25-35); C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3