Elsevier

Brain Research

Volume 912, Issue 2, 7 September 2001, Pages 128-136
Brain Research

Research report
Progressive brain dysfunction following intracerebroventricular infusion of beta1–42-amyloid peptide

https://doi.org/10.1016/S0006-8993(01)02704-4Get rights and content

Abstract

The behavioral, neurochemical and histological changes of rats subjected to 3 days treatment with intracerebroventricular infusion of beta-amyloid peptides(Aβ)(1–42) were investigated 20 days and 80 days after the surgery. Aβ(1–42) produced a dose-dependent and a time-dependent impairment in the spontaneous alternation performance in the Y-maze (spatial working memory), place navigation task in a water maze (spatial reference memory) and passive avoidance retention (non-spatial long-term memory) at doses of 10 and 20 μg/rat. The learning impairments were more severe at 80 days than 20 days after infusion of Aβ(1–42). At 25 days after the infusion, a significant decrease in hemicholinium-3 (HC-3) binding was observed only in the hippocampus, although choline acetyltransferase (ChAT) activity was unchanged in the brain regions tested as compared with the vehicle (Aβ40–1) treatment. In contrast, the reduction in ChAT activity 85 days after Aβ(1–42) infusion was significant in hippocampus and striatum. HC-3 binding was also significantly decreased in the posterior cortex, hippocampus and striatum. In the histological analysis, brain atrophy was observed inasmuch as ventricular enlargement and neuronal damage in the CA1 area of the hippocampus were seen 85 days after Aβ(1–42) infusion. These results suggest that the rats subjected to intracerebroventricular infusion of Aβ(1–42) suffered from progressive brain dysfunction, and could be useful as an animal model for evaluating the developmental processes at the early and/or middle stage of Alzheimer’s-type dementia.

Introduction

Alzheimer’s disease (AD) is characterized by the formation of neurofibrillary tangles and deposition of beta-amyloid (Aβ) protein, the major extracellular component of AD plaques [20], [30]. Aβ is a 39–43-amino acid peptide derived from the amyloid β-protein precursor (APP) [16]. The extent of Aβ deposition correlates with the degree of neuronal damage and cognitive deficits [5], [19]. Since a report by Yankner et al. indicating that Aβ fragments are neurotoxic to cultured rat cortical and/or hippocampal neurons, primary culture systems have been utilized as an in vitro model for investigating the effects of Aβ [36]. However, the effects of Aβ injection into the parenchyma and/or cerebroventricular have been controversial. Microinjection of Aβ into the cortex, hippocampus or amygdala has been reported to produce neuron loss, cholinergic degeneration [2], [6], [17], [31], [34], and no neurotoxic effect [3], [8], [28], [29], [35].

AD involves progressive memory loss and dementia, a severe loss of basal forebrain cholinergic neurons and a significant decrease in both the cortical and hippocampal choline acetyltransferase (ChAT) activity and acetylcholine content [4], [32].

Hoshi et al. have demonstrated that Aβ(1–42) freshly solubilized in water (soluble Aβ1–42) but not soluble Aβ(1–40) suppressed synthesis of acetylcholine in cholinergic neurons at very low concentrations (10–100 nM), although soluble Aβ(1–42) is not neurotoxic to primary septal cultures [15]. Alud et al. reported that low concentrations of Aβ can induce cholinergic hypoactivity without apparent neurotoxicity [1]. Harkany et al. have shown correlative in vitro and in vivo evidence that an excitotoxic cascade mediates Aβ neurotoxicity in the rat magnocellular nucleus basalis [12].

Rat given a intracerebral injection of Aβ have been frequently used as an animal model for AD-type amnesia. For example, Maurice et al. have reported that impairments of the passive avoidance and water maze task measured 7 and/or 14 days after a single intracerebroventricular (i.c.v.) injection of aged Aβ(25–35) were observed in mice [21]. In another experiment, Nitta et al. found an impairment of water maze performance and a significant reduction in ChAT activity in the frontal cortex and hippocampus after i.c.v. infusion of soluble Aβ(1–40) for 2 weeks [25]. In a recent study, Harkany et al. demonstrated that intra-nucleus basalis injection of β-amyloid(Phe(SO3H)24)25–35 greatly impaired the step-through passive avoidance paradigm but not spatial learning processes (Morris water maze learning abilities) [14]. However, there have been few attempts to investigate the progressive brain dysfunction induced by intracerebroventricular infusion of β-amyloid peptides.

Consequently, in the current study, we focused on the developmental processes of behavioral function, and neurochemical and histological changes induced by intracerebroventricular infusion of Aβ(1–42) as an in vivo model of AD-type amnesia. We show that progressive memory deficits and neuronal dysfunction were produced after infusion of Aβ(1–42) into the cerebral ventricles in adult rats.

Section snippets

Animals

Male Fischer 344 rats (Charles River, Japan Breeding Laboratories), aged 18 to 20 weeks and weighing 320–360 g at the beginning of the experiments, were used in this study. Rats were housed in a climate-controlled room (23±1°C and 55±5% humidity) with food and water available ad libitum, under a 12 h light/dark cycle (light on at 7.00 a.m.). Experiments were carried out between 9.00 a.m. and 4.00 p.m.

Surgery

The Aβ(1–42) and Aβ(40–1) peptides (ANASPEC Inc., San Jose, CA 95131, USA) were dissolved in

Spontaneous alternation performance

As shown in Fig. 1, the percentage of spontaneous alternation (%SA) in rats infused i.c.v. with the vehicle (Aβ40–1 amyloid peptide; 20 μg) was 75–78%. In contrast, rats treated with Aβ(1–42) exhibited dose-dependent learning deficits without a change in total arm entries (F=10.573, P=0.005; F=8.140, P=0.017, respectively) (Fig. 1A,C). Post-hoc analysis revealed that performance in the Aβ(1–42)-infused groups at the higher dose was significantly impaired. However, no significant change was seen

Discussion

We investigated the effects of intracerebroventricular infusion of Aβ(1–42)using an osmotic mini-pump (for 3 days) on the developmental processes of behavioral function, as well as neurochemical and histological changes.

In behavioral testing, Aβ-treated rats showed dose- and time-dependent cognitive deficits in both spontaneous alternation performance in the Y-maze (spatial working memory) and place navigation task in a water maze (spatial reference memory). Furthermore, the learning

Acknowledgements

We are grateful to Dr G. Nakayama (Director) for his support and encouragement throughout this study. We also thank Misses Hirose and Ogino for their excellent technical assistance.

References (36)

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