Dissecting the role of Corticotropin-releasing hormone receptor type 1 in Alzheimer's Disease

In Alzheimer's Disesase (AD) several alterations of the Corticotropin-releasing hormone (CRH) system have been reported and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis have been shown to increase Amyloid β (Aβ) production. To shed light on the involvement of CRH in AD related processes in vivo, we bred APP over-expressing mice (arcAβ mice, Knobloch et al. 2007) to conventional CRH receptor type 1 (CRH-R1) knockout (R1KO) mice (Timpl et al. 1998). Four different genotypes were obtained (wildtype (wt), arcAβ transgenic (tg), R1KO and tg R1KO), which have been comprehensively phenotyped involving behavioural analyses, neuropathology and biochemistry at the age of 4, 8 and 12 months. Basal emotionality of mice was evaluated at 4 and 12 months of age using open field, elevated plus maze, dark-light box and forced swim test. Tg mice showed increased locomotor activity compared to non-tg mice. The previously shown reduced anxiety-like behaviour of R1KO mice could partly be reproduced. Cognitive abilities were evaluated using object recognition (OR) and water cross maze (WCM) task. The R1KO compensated cognitive deficits of tg mice in the OR test. In the WCM the decline of performance was observed to be correlated with age. Moreover, tg mice showed strong cognitive deficits. Interestingly, tg and tg R1KO mice developed different strategies to accomplish the task. Preliminary biochemical analyses suggest a reduction of Aβ levels in tg R1KO compared to tg mice.