Neuropeptides in hippocampus and cortex in transgenic mice overexpressing V717F beta-amyloid precursor protein - Initial observations

lmmunohistochemistry was used to analyse 18- and 26-month-oId transgenic mi ce overexpressing the human beta-amyloid precursor protein under the platel et-derived growth factor-beta promoter with regard to presence and distribu tion of neuropeptides. In addition, antisera/antibodies to tyrosine hydroxy lase, acetylcholinesterase, amyloid peptide, glial fibrillary acidic protei n and microglial marker OX42 were used. These mice have been reported to ex hibit extensive amyloid plaques in the hippocampus and cortex [Masliah et n l. (1996) J. Neurosci. 16, 5795-5811]. The most pronounced changes were related to neuropeptides, whereas differen ces between wild-type and transgenic mice were less prominent with regard t o tyrosine hydroxylase and acetylcholinesterase. The main findings were of two types; (i) involvement of peptide-containing neurites in amyloid beta-p eptide positive plaques, and (ii) more generalized changes in peptide level s in specific layers, neuron populations and/or subregions in the hippocamp al formation and Ventral cortices. In contrast, the parietal and auditory c ortices were comparatively less affected. The peptide immunoreactivities mo st strongly involved, both in plaques and in the generalized changes, were galanin, neuropeptide Y, cholecystokinin and enkephalin. This study shows that there is considerable variation both with regard to p laque load and peptide expression even among homozygotes of the same age. T he most pronounced changes, predominantly increased peptide levels, were ob served in two 26-month-oId homozygous mice, for example, galanin-, enkephal in- and cholecystokinin-like immunoreactivities in stratum lacunosum molecu lare, and galanin, neuropeptide Y, enkephalin and dynorphin in mossy fibers . Many peptides also showed elevated levels in the ventral cortices. Howeve r, decreases were also observed. Thus, galanin-like immunoreactivity could not any longer be detected in the diffusely distributed (presumably noradre nergic) fiber network in all hippocampal and cortical layers, and dynorphin -like immunoreactivity was decreased in stratum moleculare, cholecystokinin -like immunoreactivity in mossy fibers and substance P-like immunoreactivit y in fibers around granule cells. The significance of generalized peptide changes is at present unclear. For example, the increase in the mainly inhibitory peptides galanin, neuropepti de Y, enkephalin and dynorphin and the decrease in the mainly excitatory pe ptide cholecystokinin in mossy fibers land of substance P fibers around gra nule cells) indicate a shift in balance towards inhibition of the input to the CA3 pyramidal cell layer. Moreover, it may be speculated that the incre ase in levels of some of the peptides represents a reaction to nerve injury with the aim to counteract, in different ways, the consequences of injury, for example by exerting trophic actions. Further studies will be needed to establish to what extent these changes are typical for Alzheimer mouse mod els in general or are associated with the V717F mutation and/or the platele t-derived growth factor-p promoter. (C) 2000 IBRO. Published by Elsevier Sc ience Ltd. All rights reserved.