Single intracerebroventricular administration of amyloid-beta (25–35) peptide induces impairment in short-term rather than long-term memory in rats
Introduction
Amyloid-beta peptide (Aβ) is the main constituent of senile plaques found in the aging brain. Increase in the number of senile plaques in brain areas linked with disturbances of learning and memory processing is characteristic of aging-associated disorders, such as Alzheimer’s disease (AD) [42]. Although the initial memory loss found in AD patients indicates the presence of early limbic dysfunction, the initial plaques tend to have a higher density in association neocortex rather than limbic structures. Moreover, there are significant mnemonic impairments in AD patients during the first few years of the disease, while the significant accumulation of Aβ in the form of plaques does not occur until much later [4]. Recently, direct correlation between Aβ load and cognitive impairments in AD patients has been reported 2., 35., though it remains difficult to explain why some individuals with a high Aβ plaques density have normal cognitive function 14., 21.. It was hypothesized that Aβ exerts its initial influence in some mobile, circulating form rather at the sites of plaque deposits. This suggestion was supported by the data from transgenic mice overexpressing mutant human amyloid precursor protein (APP) [23] as well as from the Tg2576 strain of transgenic mice [55] by demonstrating that small assemblies of Aβ, occurring as intermediates during Aβ plaque formation, disrupt cognition in these mice rather than insoluble Aβ deposits themselves.
Though effects of Aβ on learning and memory processes have been extensively studied using different experimental in vivo and in vitro approaches, the influence of Aβ on cognitive function is not completely understood. Cognitive deficit has been well documented both in transgenic mice overexpressing mutant human APP 20., 55. and in rodents with centrally administered Aβ. Most injection models were performed using synthetic peptide Aβ(1–40) or Aβ(1–42) analogous to peptides found in neuritic plaques in AD patients. Intracerebral injections of Aβ-related peptides to mice or rats impair the learning and retention of active 16., 31. or passive 18., 19. avoidance, as well as discrimination learning in a Y-maze 30., 31.. Although chronic intrahippocampal injection of Aβ(1–40) did not influence performance of a standard task in the 8-arm radial maze [31], it did disrupt working memory tested in the same maze [49]. However, intracerebroventricular (i.c.v.) infusion of Aβ(1–40) impaired water-maze learning [36] and working memory tested in the radial maze [52].
Potent amnesic properties were also reported for the 11-amino acid fragment of Aβ, Aβ(25–35). Aβ(25–35) is a subset of Aβ(1–42) located at the C-terminal end in the hydrophobic domain. This short peptide has been proposed to be a functional domain of Aβ responsible for its neurotoxic properties 41., 57.. Maurice et al. [29] showed that i.c.v. injection of Aβ(25–35) impaired spontaneous alternation behavior, water-maze learning, and passive avoidance in mice. Moreover, this group demonstrated that injection of aggregated Aβ(25–35) had more prominent effects on animal behavior compared to its non-aggregated form 13., 29.. In rats, acute i.c.v. administration of aggregated Aβ(25–35) also induced amnesia 13., 45., 56.. Behavioral disturbances induced by Aβ(25–35) were also demonstrated in experiments with intraseptal [50] or intrahippocampal [7] injections of the peptide.
The behavioral deficits in Aβ(25–35)-injected animals were accompanied by neuronal lesions, neurodegeneration, and glial response 18., 29., 46.. Aβ(25–35)-induced memory disturbance correlated with cholinergic deficits indicated as loss of cholinergic fibers [38], decline in choline acetyltransferase activity in the medial septum, cortex, and hippocampus, a decrease in the number of choline acetyltransferase-immunoreactive cells in the medial septum [56] and a reduction of nicotine-evoked acetylcholine release from the frontal cortex and hippocampus [37].
The aim of this study was a systematic investigation of the effect of a single aggregated Aβ(25–35) i.c.v. injection on spatial and non-spatial short- and long-term memory (with particular emphasis to long-term effects) to further investigate the relationship between aggregated Aβ(25–35) and learning and memory function in rats.
Section snippets
Animals
Sixty-three young adult male Wistar rats were supplied by Stolbovaya Breeding Center (Russian Academy of Medical Sciences). Animals, weighing 230–290 g at the beginning of the experiment, were housed five per cage at 12:12 h light/dark cycle (08.00–20.00 h) and fed ad libitum. The experiments were done in accordance with the European Communities Council Directive (86/609/EEC) for the care and use of animals for experimental procedures; protocol was approved by the local Animal Care and Ethics
Results
Spontaneous alternation behavior reflects a spatial working memory capacity, though in a primitive form, since it is based on the ability of animals to enter an arm of the Y-maze not entered in the previous choices. Rats were tested in the Y-maze 17, 36, and 180 days after surgery. The bilateral administration of aggregated Aβ(25–35) into the cerebral ventricles resulted in a significant decrease in alternation behavior at all time points studied (Fig. 1A). This effect was dependent on the
Discussion
In the present study, we demonstrated that a single i.c.v. administration of aged Aβ(25–35) to Wistar rats (15 nmol/rat) resulted in a marked amnesic effects, evidenced as deficiency in short-term but not long-term memory. The aggregated Aβ(25–35) induced the impairment of spontaneous alternation behavior (index of spatial working memory) in a Y-maze 17, 36, and 180 days after i.c.v. administration of the peptide. Similarly, Aβ(25–35) impaired memory in an olfactory social recognition test, an
Acknowledgements
This study was supported by Russian Basic Research Foundation (Grant #01-04-49477a), Russian Academy of Sciences grant for young investigators (#294), and Russian Academy of Sciences Program “Fundamental Medicine—2003”.
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