These observations underscore the importance of aB-crystallin in diseases of aging and protein aggregation, but their importance in mouse models has not been examined. To this end, we examined behavioral deficits when AD model mice were crossed mice lacking aB-crystallin/ HspB2. Older knockout mice consistently lost weight and body fat and subsequently developed severe spine curvature and skeletal muscle degeneration. The importance of sHsps in mice experiencing an increased proteotoxic stress was previously not studied. In this report, we inter-crossed between mice lacking aB-crystallin/HspB2 and Tg2576 transgenic mice, which over-produces the highly aggregation-prone amyloid-beta. We observed that chaperonedeficient transgenic mice developed severe locomotion defects compared to mice with either chaperone deficiency alone or transgene expression alone. Our results show that exacerbation of protein aggregation and loss of chaperones produced a new synthetic phenotype of motor defects in mice. In this study, we aimed to investigate the effect of chaperonedeficiency in a mouse model for AD. When expression of APP was combined with loss of aB-crystallin/HspB2, we observed that new phenotypes involving locomotion and sensory function deficits were revealed. Neither loss of aB-crystallin/HspB2 nor transgenic expression of APP by themselves produced these phenotypes. The synthetic sick phenotypes underscore a negative synergy between expression of APP, which is thought to increase the production of the aggregation-prone Ab peptide and reduced chaperone function. When misfolding-prone proteins are overproduced, cellular health may depend on its ability to also overproduce chaperones. In AD brains, where the load of misfolded proteins is high, others have observed that aB-crystallin expression was high in glial cells in areas surrounding plaques and tangles. However, we observed that aB-crystallin levels in brain lysates decreased in an age-dependent manner in transgenic AD model mice compared to non-transgenic littermates. The contrasting observations may be attributed to the differences in methods – while others have monitored relatively small regions by immunohistochemistry in human AD brains, we monitored the expression levels by immunoblotting lysates from the entire brains of a mouse model for AD. In this regard, we would like to point out that other studies have observed no significant differences in the expression of aBcrystallin in various regions of AD brains by immunoblotting methods, by mass spectrometry based protein identification methods and by immunohistochemical methods. Further, we speculate that the difference between the human and mouse results could be due to differential cellular responses towards the entire gamut of Rapamycin pathologies in AD brains versus the predominantly plaque pathology in the AD model mice used in this study. However, the exact reasons for these observations are presently unclear and require further experimentation.