Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis

Mice were tested at three, six, and 12 months of age, which corresponds to early, mild, and severe Aβ plaque deposition, following a cross-sectional experimental design. We used a delay version of the fear conditioning paradigm in which tone stimulus was co-terminated with foot-shocks during exploration of the training chamber. The Aβ plaque burden was evaluated at each age after the completion of the behavioral tests.CRDN8 mice showed context fear memory comparable to control mice at three and six months, but were significantly impaired at 12 months of age. In contrast, the tone fear memory was significantly impaired in the model at each age of testing. The Aβ plaque burden significantly increased with age, and was correlated with the overall impairment in context and tone fear memory in the CRND8 mice within the studied age.Our data extend previous studies showing that other APP mouse models exhibit impairment in fear conditioned memory, by demonstrating that this impairment is progressive and correlates well with an overall increase in Aβ burden. Also, the demonstrated greater sensitivity of the tone conditioning test in the identification of age dependent differences between CRND8 and control mice suggests that this paradigm might be particularly suitable in studies evaluating potential therapeutics related to memory improvement in mouse models of amyloidosis.Alzheimer's disease (AD) is the leading cause of dementia in the elderly, affecting more than 35 million people worldwide [1]. Currently, confirmation of a clinical diagnosis of AD still requires post mortem identification of parenchymal amyloid beta (Aβ) deposits and intra-neuronal neurofibrillary tangles composed of abnormally phosphorylated tau protein [2-5] and severe loss of brain tissue [6-8]. In the near future, cerebrospinal fluid (CSF) measures of Aβ and tau or amyloid imaging may be utilized to provide pre-mortem confirmation of the AD diagnosis. Senile amyloid plaques are found in large numbers i