Long-Term Treatment with Lithium Alleviates Memory Deficits and Reduces Amyloid-beta Production in an Aged Alzheimer's Disease Transgenic Mouse Model

The glycogen synthase kinase-3 beta (GSK3 beta) pathway plays a central role in Alzheimer's disease (AD) and its deregulation accounts for many of the pathological hallmarks of AD. Lithium, which modulates GSK3 beta activity, has been shown to reduce amyloid production and tau phosphorylation in pre-pathological AD mouse models. In this study, we investigated the effects of chronic LiCl treatment in aged double transgenic mice (A beta PP(Swe)/PSI(A246E)). We found that chronic lithium treatment decreased the gamma-cleavage of amyloid-beta protein precursor, further reduced amyloid-beta production and senile plaque formation, accompanied by the improvement in spatial learning and memory abilities. Because autophagy may play an important role in the pathology of AD, we also assessed the autophagy activity and found that the chronic lithium treatment attenuated the autophagy activation in this AD mouse model. Our results suggest that prolonged lithium treatment, even during the later stages of AD, could be an effective therapeutics.