Learning deficits occurs prior to memory retrieval impairment in female Senescence Accelerated Mouse (SAMP8)

The most regularly used mouse models of Alzheimer's disease in drug development include APP/PS1, 3xTg, and 5xFAD mice. This is a limitation as all these mice represent familial AD. Given sporadic AD accounts for the majority of the AD cases in human, there is an unmet need to validate potential rodent models to better represent sporadic AD. SAMP8 is a naturally-occurring mouse line that displays many characteristics identified in Alzheimer's disease (AD) patients, such as learning and memory deficits, and accumulation of beta-amyloid. In people with preclinical AD, deficits in learning manifest faster than decline in memory retrieval. It is unclear if SAMP8 mice also exhibit this feature, and therefore the current study aims to determine if this feature can be observed in SAMP8, to support the use of SAMP8 as a mouse model of sporadic AD for drug development.The cognitive function of SAMP8 mice and their age-matched non-AD control SAMR1 mice (at various ages) were assessed using Y maze spatial memory test, with 3-10 min training duration and 1.5-3 h interval between training and testing session.At 3-4 months old, SAMP8 but not SAMR1 failed to differentiate the novel arm from familiar arm in a standard Y maze test (3 min training, 3 h interval). When training time was increased to 10 min, SAMP8 passed the test, while increased training time did not affect the performance of SAMR1 mice. These data indicated that longer training time is required by SAMP8 than SAMR1 to achieve the expected performance, suggesting the presence of learning deficits in SAMP8. Interestingly, at 6-7 months old, though both SAMP8 and SAMR1 received 10-min training, only SAMR1 passed the test. The performance of SAMP8 mice was successfully improved by shortening the interval between training and testing (from 3 h to 1.5 hr). These data indicate a deteriorated memory retention capability and a possible impairment in memory retrieval in SAMP8.Overall, this study has provided supportive evidence that learning deficits occurs prior to memory retrieval impairment in SAMP8, and the use of SAMP8 as mouse model for AD.