Molecular Brain Research 80 (2000) 188–197 www.elsevier.com / locate / bres Research report Spatiotemporal expression of BDNF in the hippocampus induced by the continuous intracerebroventricular infusion of b-amyloid in rats a,b a b b a Ya-Ping Tang , Kiyofumi Yamada , Yasuhiko Kanou , Takashi Miyazaki , Xiao-Li Xiong , b b b a, * Fukushi Kambe , Yoshiharu Murata , Hisao Seo , Toshitaka Nabeshima a Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8560, Japan b Department of Endocrinology and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya 466-8560, Japan Accepted 20 June 2000 Abstract The b-amyloid protein (Ab) is the major component of senile plaques found in the brain in Alzheimer’s disease (AD). Its neurotoxic properties in vivo, however, are not well defined. Since the expression of neurotrophin genes is considered an important component of the intrinsic neuroprotective response to insults, we analyzed the gene expression of neurotrophins in the brains of rats which received a continuous infusion of Ab-(1–42) into the cerebroventricle. Northern blot analysis revealed a significant increase in brain-derived neurotrophic factor (BDNF) expression in the hippocampus but no change in the cerebral cortices. The alteration peaked on days 3–7 and returned to the basal level on day 14 after the start of Ab-(1–42) infusion. No significant changes in nerve growth factor or neurotrophin-3 mRNA expression were observed. The infusion of Ab-(1–40) and (25–35) also triggered the expression of BDNF mRNA, whereas neither Ab-(40–1) nor (1–16) had any effect. In situ hybridization histochemistry revealed that the expression mainly occurred in the hilus and granular layer of the dentate gyrus and to a lesser extent in the pyramidal neurons of the CA1 region. These results demonstrate that the continuous intracerebroventricular infusion of Ab induces selective and spatiotemporal expression of BDNF mRNA in the hippocampus.  2000 Elsevier Science B.V. All rights reserved. Theme: Degenerative disease Topic: Alzheimer’s — beta amyloid Keywords: Alzheimer’s disease; b-Amyloid; Neurotoxicity; Hippocampus; Brain-derived neurotrophic factor 1. Introduction are associated with the development of AD, enhance either b- or g-secretase cleavage of APP to overproduce Ab Alzheimer’s disease (AD) is the most common cause of [5,10]. Second, overexpression of human APP and pre- progressive decline of cognitive function in aged humans, senilin genes with mutations found in AD replicates most and is characterized by the presence of numerous senile of the abnormality associated with AD, including deposit plaques and neurofibrillary tangles. The senile plaques are of Ab, neuronal death, gliosis, and memory impairments composed of b-amyloid peptides (Ab), 39–42 amino acid [11,13,19,20,52]. Third, Ab is neurotoxic in vitro [4,73]. peptide fragments of the b-amyloid precursor protein Attempts to replicate Ab neurotoxicity in vivo have (APP) [25,37]. Several lines of evidence support the Ab yielded conflicting results. Some studies [8,9,39,56], in- cascade hypothesis in AD although the etiology and cluding ours [22,23,43,44,68,70], have demonstrated the in pathogenesis is not well understood [15,16,53,65]. vivo neurotoxicity of Ab whereas others failed to confirm First, mutations in either APP or presenilin genes, which it [7,14,48,64]. Most of those studies examined either behavioral and neurochemical consequence or neurode- generation after injection of Ab into the brain [65,71]. An *Corresponding author. Tel.: 181-52-744-2674; fax: 181-52-744- alternative approach, by which Ab neurotoxicity in vivo 2682. E-mail address: tnabeshi@med.nagoya-u.ac.jp (T. Nabeshima). can be detected more sensitively, would further our 0169-328X / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0169-328X(00)00158-3