Impaired satiation and increased feeding behaviour in the triple-transgenic Alzheimer's disease mouse model.

Abstract

Alzheimer's disease (AD) is associated with non-cognitive symptoms such as changes in feeding behaviour that are often characterised by an increase in appetite. Increased food intake is observed in several mouse models of AD including the triple transgenic (3×TgAD) mouse, but the mechanisms underlying this hyperphagia are unknown. We therefore examined feeding behaviour in 3×TgAD mice and tested their sensitivity to exogenous and endogenous satiety factors by assessing food intake and activation of key brain regions. In the behavioural satiety sequence (BSS), 3×TgAD mice consumed more food after a fast compared to Non-Tg controls. Feeding and drinking behaviours were increased and rest decreased in 3×TgAD mice, but the overall sequence of behaviours in the BSS was maintained. Exogenous administration of the satiety factor cholecystokinin (CCK; 8-30 µg/kg, i.p.) dose-dependently reduced food intake in Non-Tg controls and increased inactive behaviour, but had no effect on food intake or behaviour in 3×TgAD mice. CCK (15 µg/kg, i.p.) increased c-Fos protein expression in the supraoptic nucleus of the hypothalamus, and the nucleus tractus solitarius (NTS) and area postrema of the brainstem to the same extent in Non-Tg and 3×TgAD mice, but less c-Fos positive cells were detected in the paraventricular hypothalamic nucleus of CCK-treated 3×TgAD compared to Non-Tg mice. In response to a fast or a period of re-feeding, there was no difference in the number of c-Fos-positive cells detected in the arcuate nucleus of the hypothalamus, NTS and area postrema of 3×TgAD compared to Non-Tg mice. The degree of c-Fos expression in the NTS was positively correlated to food intake in Non-Tg mice, however, this relationship was absent in 3×TgAD mice. These data demonstrate that 3×TgAD mice show increased feeding behaviour and insensitivity to satiation, which is possibly due to defective gut-brain signalling in response to endogenous satiety factors released by food ingestion.