Amyloid-β(25–35)-induced memory impairments correlate with cell loss in rat hippocampus
Introduction
Amyloid β-peptide (Aβ) plays an important role in the pathophysiology of Alzheimer's disease [1]. A large body of experimental data has demonstrated that Aβ injected intracerebroventricularly to rodents significantly influences their cognitive function. It has been shown that single intracerebroventricular administration of Aβ(l–40) or of the undecapeptide Aβ(25–35), possessing neurotoxic properties of the natural peptide, induces impairment of spontaneous alternation behavior [2], [3], water maze learning [2], and passive avoidance [2] in mice as well as spontaneous alternation behavior [4], [5], water maze and radial maze learning [7], [8], [9], passive avoidance [9], and social recognition [5], [6] in rats. Chronic intracerebroventricular infusion of Aβ(l–40) also impaired learning and memory in rats [10], [11], [12].
The dysfunction and degeneration of cholinergic neuronal circuits in the brain is a prominent feature of Alzheimer's disease [1], [13]. Cholinergic deficit has been reported as a result of Aβ administration [14], and cognitive dysfunction observed in rodents after a single injection or chronic intracerebroventricular infusion of Aβ is suggested to be due, at least in part, to cholinotoxic properties of the peptide [9], [12]. Administration of cholinergic agonist (nicotine) or acetylcholinesterase (AchE) inhibitor (tacrine) significantly improved learning and memory impaired by intracerebroventricular injection of Aβ(25–35) [2].
There is much evidence that oxidative damage plays a causative role in Alzheimer's disease and in Aβ-induced toxicity [15], [16], [17]. In vitro data suggest that Aβ(25–35) neurotoxicity may be related to the activation of various free radical-mediated processes [18], [19]. Direct infusion of Aβ peptides into rat brain through a microdialysis probe increased production of reactive oxygen species in an NMDA receptor- and nitric oxide (NO)-dependent manner [20]. Recent in vitro data also suggested the role of NO in neurotoxic effects of Aβ(25–35) [19].
Although neurotoxic effects of Aβ are well documented and recognized [1], [17], [21], only few studies have demonstrated direct neuronal damage after a single Aβ injection into the cerebral ventricles. Neuronal cell loss in the hippocampus and cerebral cortex in mice 21 days [2] and in rats 185 days after the single intracerebroventricular administration of Aβ(25–35) [5] has been reported.
The aim of the present study was to investigate the relationship between Aβ(25–35)-induced memory impairments in rats and neurodegeneration in the CA1 and CA3 subfields of the hippocampus. To study whether oxidative stress participates in Aβ(25–35)-induced neurodegeneration and memory dysfunction, we measured lipid peroxidation level and superoxide anion–radical generation/scavenging in the hippocampus within 1 month after intracerebroventricular injection of the peptide.
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Animals
Sixty-six adult male Wistar rats (Stolbovaya Breeding Center, Moscow region, Russia) weighing 230–290 g at the beginning of the experiment were used as subjects in this study. Rats were housed three to five per cage under a 12:12-h light–dark cycle (lights on at 8:00 a.m.); food and water were available ad libitum in the home cages. The experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and our protocol was
Effects of Aβ(25–35) on rat behavior in a radial maze
A two-way ANOVA with repeated measures was applied to analyze the number of RM errors made by rats during the learning of the task in the radial maze. Both vehicle-treated and Aβ(25–35)-treated animals demonstrated the ability to improve their behavior during the learning session. A significant trial effect on the number of RM errors was found when all the data from both groups were analyzed together [F(29,319)=1.74, P<.04]. For further analysis, all RM errors were divided into six blocks of
Discussion
Numerous laboratories have used the smaller 11-amino acid fragment of the full-length peptide, Aβ(25–35), as a convenient alternative in Alzheimer's disease investigations since the smaller peptide mimics several of the toxicological and oxidative stress properties of the native full-length peptide. In the present paper, we have demonstrated that a single intracerebroventricular administration of Aβ(25–35) induced significant impairment in rat behavior in the radial maze. The radial maze task
Acknowledgments
This study was supported by the RBRF grants #01-04 4947, #01-04 49476, Russian Academy of Sciences grant for young investigators #294, and Russian Academy of Sciences grant “Fundamental Medicine-2003.”
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