n-(n-(3-5-difluorophenacetyl)alanyl)phenylglycine-tert-butyl-ester and Memory-Disorders

Synaptic loss is the best pathological correlate of the cognitive decline in Alzheimer's disease; however, the molecular mechanisms underlying synaptic failure are unknown. We found a non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines and an enhancement of this activity at the onset of memory decline in the Tg2576-APPswe mouse model of Alzheimer's disease. In spines, caspase-3 activated calcineurin, which in turn triggered dephosphorylation and removal of the GluR1 subunit of AMPA-type receptor from postsynaptic sites. These molecular modifications led to alterations of glutamatergic synaptic transmission and plasticity and correlated with spine degeneration and a deficit in hippocampal-dependent memory. Notably, pharmacological inhibition of caspase-3 activity in Tg2576 mice rescued the observed Alzheimer-like phenotypes. Our results identify a previously unknown caspase-3-dependent mechanism that drives synaptic failure and contributes to cognitive dysfunction in Alzheimer's disease. These findings indicate that caspase-3 is a potential target for pharmacological therapy during early disease stages.

Topics: Alzheimer Disease; Animals; Calcineurin; Caspase 3; Caspase Inhibitors; Dendritic Spines; Dipeptides; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Long-Term Synaptic Depression; Memory Disorders; Mice; Mice, Transgenic; Nerve Degeneration; Oligopeptides; Polyglutamic Acid; Receptors, AMPA; Synaptic Transmission