MEMORY IMPAIRMENTS IN ALZHEIMER'S DISEASE MOUSE MODELS

Case Western Reserve University, Cleveland OH

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Abstract

While numerous rodent models of AD have been examined by spatial motor tasks such as the water maze, the specific relevance of this test to AD remains unclear, as spatial memory impairments are typical of only later stage AD. In order to examine transgenic mouse models for memory impairments typically found early in AD, several different APP and PS-1 YAC transgenic mice lines as well as a well-defined cDNA-based APP transgenic mouse line (Tg2576) will be compared with late-onset APOE transgenic mice for pathological and behavioral differences in both simple and conditional odor-discrimination tasks. In the simple odor- discrimination task, mice must learn to associate which odor/sand mixture (e.g. cumin) contains a cereal reward, while the other odor/sand mixture (e.g. cocoa) contains no reward. The mice will be trained on three different odor pairs (e.g. marjoram vs. paprika and thyme vs. ginger) for a total of ten trials spread across three days. This task is unique in that we can see the exact moment memory becomes impaired by either retrograde amnesia for one of the 3 odor discriminations or impaired learning of the odor discriminations, as measured on the last day of training. The mice will be tested for retrograde amnesia by imposing an 8, 14, or 21-day retention interval for each respective odor pair. Memory will be measured by first choice reponses and time (in seconds) spent digging in each odor cup. Five groups of animals will be tested, four cross-sectional (at 12, 18 and 24 months of age) and one longitudinally until 24 months of age. The same groups will also be tested in the conditional odor-discrimination task, where mice must associate their internal hunger state with the correct odor to retrieve a cereal reward. Thus, mice must learn that when they are food deprived they must dig in cocoa and when satiated, dig in cumin. Animals will be trained for 17 days and tested on days 18 and 19 in each satiation level around 24 months of age. It is hypothesized that at the time we begin to see memory impairments (around 14 months of age), Abeta deposits should be noticeable by histological analysis and when the animals are older (24 months) the pathology should be much worse as correlated with greater impairment on both the simple and conditional odor-discrimination tasks.