Novel cage stress-induced improvement of early alzheimer’s-like changes in tastpm mice is unrelated to changes in brain endocannabinoids levels

Marie-Christine Pardon, Sarir Sarmad, Ivan Rattray, Thimothy Bates, Gillian Scullion, Charles A Marsden, David A Barrett, David A Kendall. University of Nottingham, Nottingham, United Kingdom.

Stress in adulthood contributes to the later development of Alzheimer’s disease (AD; Mejia et al., 2003). The brain endocannabinoid system is involved in the stress response (Patel et al. Endocrinology 145:5431-5438, 2004), is thought to play a role in the pathogenesis of AD (Pazos et al., 2004), and therefore, may be involved in stress-induced precipitation of AD. Here we assessed the effects of adulthood stress on the development of early AD-related pathological markers in double transgenic mice over-expressing amyloid (TASTPM mice) and on regional levels of endocannabinoids in the brain. A first group of 4 month-old TASTPM (23-25g) and C57Bl/6 (28-30g) male mice was assessed for the acquisition, short-term memory and extinction of contextual fear conditioning (CFC). A second group of 4-month old TASTPM and C57Bl/6 male mice was subjected to 5 weeks of repeated psychological stress (novel cage) and then compared with unstressed mice for performance in the CFC. In all mice, levels of soluble and insoluble amyloid and levels of endocannabinoids (anandamide AEA; 2-arachidonylethanolamine 2-AG; oleoylethanolamide OEA; palmitoylethanolamide PEA), were measured in the hippocampus and frontal cortex. Repeated novel cage stress prevented the onset of short-term memory deficit seen in 5.5-month old TASTPM mice, without reversing the deficit in extinction already seen at 4-months old. Regional levels of soluble and insoluble amyloid were reduced by stress in TASTPM. However, chronic stress did not influence the age-related increase in regional brain endocannabinoids levels seen between 4 and 5.5 months in TASTPM mice for all four endocannabinoids assayed in the frontal cortex of mice (p<.01 in all cases), and which was exacerbated in TASTPM mice for AEA, OEA and 2-AG despite a lack of basal differences between the two genotypes at 4 months old (table 1). In the hippocampus, there were no differences in endocannabinoid levels between TASTPM and C57BL/6 mice and no effects of stress, but an age-related decrease in OEA (p=.05) and PEA (p<.05) levels and an age-related increase in 2-AG (p<.0001) levels were observed. To date, the role of endocannabinoids in AD is largely unknown and may seem contradictory. In the light of recent studies, one possibility is that elevations of endocannabinoids levels are, in fact, part of a neuroprotective mechanism aimed at counteracting amyloid-related brain damage rather than part of the pathological process. On the other hand, endocannabinoids are known for their disruptive effects on memory and for facilitating memory extinction and, as such, are thought to contribute to cognitive dysfunction in AD. This, however, contrasts with our results. In fact, in TASTPM mice, the extinction deficit was present prior to the elevation of endocannabinoid levels and, if such elevations occurred together with the onset of short-term memory deficits, the improvement of memory by stress was not associated with an effect on endocannabinoid levels. Thus, the role of the endocannabinoid system in the early stages of AD-like pathology needs to be further investigated. Supported by a University of Nottingham BRC strategic fellowship to MCP and GlaxoSmithKline who provided the mice.

Mejia et al. Int Psychogeriatr 15:337-349, 2003; Pazos et al. Life Sci 75:1907-1915, 2004