Research reportProgressive brain dysfunction following intracerebroventricular infusion of beta1–42-amyloid peptide
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.
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