Neuropeptide alterations in the hippocampal formation and cortex of transgenic mice overexpressing β-amyloid precursor protein (APP) with the Swedish double mutation (APP23)

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The role of neuropeptides and the significance of peptidergic mechanisms in neurodegenerative diseases are still unclear. In the periphery, nerve injury results in dramatic changes in the expression of neuropeptides. An important question regards to what extent similar changes occur, and similar mechanisms operate, after lesions and/or degeneration in the brain. The purpose of this work is, therefore, to study neuropeptides with regard to their presence and distribution in the APP23 mouse (HuAPP 751 K670M/N671L under the murine Thy-1 promoter), a model for Alzheimer's disease, or cerebral amyloidosis, using the immunohistochemical technique. In addition, tyrosine hydroxylase and acetylcholinesterase were analyzed. This study shows marked neuropeptide changes in the hippocampal formation and the ventral cortex, whereas the dorsolateral neocortex was less affected. There was a considerable variation with regard to peptide expression among animals of the same age which was related to the variation in Aβ deposition. Dystrophic and varicose fibers containing galanin, neuropeptide Y, enkephalin, and especially cholecystokinin were commonly seen in close proximity to amyloid plaques. In addition, generalized changes were observed, such as increases of enkephalin and neuropeptide Y in stratum lacunosum moleculare and of neuropeptide Y, enkephalin, and dynorphin in mossy fibers. In contrast, cholecystokinin was decreased in mossy fibers. Comparatively small differences were observed between wild-type and transgenic mice with regard to tyrosine hydroxylase (noradrenergic but also dopaminergic fibers) and acetylcholine esterase (mainly cholinergic fibers). The increase of neuropeptides in dystrophic fibers in this model may represent a response to nerve injury caused by the amyloid accumulation and may reflect attempts to counteract degeneration by initiating protective and/or regenerative processes.