Research reportMaternal separation exacerbates Alzheimer’s disease-like behavioral and pathological changes in adult APPswe/PS1dE9 mice
Introduction
Alzheimer’s disease (AD) is a progressive, irreversible brain disorder which is clinically characterized by an accelerated loss of memory and deterioration of other cognitive functions, including learning ability [1], [2]. With the elderly population increasing steadily, AD is becoming a huge emotional and economic burden on the patients, their families and the society as a whole [3], [4].
Senile plaques and loss of cholinergic neuron are two neuropathological hallmarks of AD [5], [6]. The principal constituent of senile plaques is amyloid-β protein (Aβ), which is generated from amyloid precursor protein (APP) and plays a crucial role in AD development [7], [8], [9], [10]. AD patients exhibit selective loss of cholinergic neurons in the brains, especially in nucleus basalis of Meynert [11]. Both the increased Aβ and loss of cholinergic neuron are believed to contribute to cognitive decline in AD [12], [13].
Although the exact etiology of AD remains unknown, clinical and animal experimental researches suggested that stress was a risk factor for AD [14], [15] and stress-related psychiatric disorders had been identified as a risk for developing AD [16], [17], [18], [19], [20], [21], [22].
Maternal separation (MS) is an animal paradigm designed to mimic repeated exposure to stress during early life [23], [24]. Stress during early life could disrupt the maternal-infants relationship and lead to long-lasting deleterious effects on brain neurodevelopment and on the network of biological systems [25]. Studies on wild type mouse and rat showed that MS could induce AD-like cognitive deficit and pathological changes [26], [27], [28], [29]. So we speculated that MS might exacerbate these abnormal changes in the AD susceptible population, especially those who had familial Alzheimer disease (FAD) inherent gene. To prove this, in the present study, APPswe/PS1dE9 double transgenic mice were used to explore the effects of MS on their behavioral and pathological changes.
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Animals
In this study, the experimental procedures involving animals were performed in accordance with the guidelines for the Regulations of the Experimental Animal Administration issued by the State Committee of Science and Technology of the People’s Republic of China. All efforts were made to minimize animals’ suffering.
APPswe/PS1dE9 mice were purchased from the Model Animal Research Center of Nanjing University (Nanjing, China). Mice were raised at 22–25 °C and 50–60% relative humidity under a 12-h
MS decreased spatial learning and memory in APPswe/PS1dE9 mice
Morris water maze tests were used to assess the spatial learning and memory functions. During spatial navigation trial, the MS and the control mice exhibited no significant differences in the first 3 days (P > 0.05). However, on day 4 and day 5, the latencies of MS mice were longer than that of control (P < 0.05, Fig. 1A).
The probe trial was performed at 24 h after the navigation trials. As shown in Fig 1B, the MS mice spent less time (15.81 ± 0.26 s) in the target quadrant (the platform quadrant in the
Discussion
Infancy is a critical period for brain development. Stress experience during this period increases Aβ level in brain [28] and exacerbates the age-related cognitive decline [38], [39]. MS rodent is a well-characterized model of early-life stress, in which pups are deprived from dam for a single or repeated periods during early life [23]. However, the effects of MS on senile plaques in cortex and cholinergic neurons in basal forebrain in AD susceptible people, e.g. in the group with family
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