leupeptins and Memory-Disorders

Reduced retrograde memory performance at the cognitive level and aggregation/deposition of amyloid beta (Aβ) in the brain at the cellular level are some of the hallmarks of Alzheimer's Disease (AD). A molecular system that participates in the removal of proteins with an altered conformation is the Ubiquitin-Proteasome System (UPS). Impairments of the UPS in wild-type (WT) mice lead to defective clearance of Aβ and prevent long-term plasticity of synaptic transmission. Here we show data whereby in contrast to WT mice, the inhibition of proteasome-mediated protein degradation in an animal model of AD by MG132 or lactacystin restores impaired activity-dependent synaptic plasticity and its associative interaction, synaptic tagging and capture (STC) in vitro, as well as associative long-term memory in vivo. This augmentation of synaptic plasticity and memory is mediated by the mTOR pathway and protein synthesis. Our data offer novel insights into the rebalancing of proteins relevant for synaptic plasticity which are regulated by UPS in AD-like animal models. In addition, the data provide evidence that proteasome inhibitors might be effective in reinstating synaptic plasticity and memory performance in AD, and therefore offer a new potential therapeutic option for AD treatment.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Cysteine Proteinase Inhibitors; Disease Models, Animal; Leupeptins; Male; Memory Disorders; Memory, Long-Term; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuronal Plasticity; Proteasome Endopeptidase Complex

Proteasomes are known to degrade proteins involved in various processes like metabolism, signal transduction, cell-cycle regulation, inflammation, and apoptosis. Evidence showed that protein degradation has a strong influence on developing neurons as well as synaptic plasticity. Here, we have shown that sulforaphane (SFN) could prevent the deleterious effects of postnatal proteasomal inhibition on spatial reference and working memory of adult mice. One day old Balb/c mice received intracerebroventricular injections of MG132 and SFN. Sham received an equal volume of aCSF. We observed that SFN pre-administration could attenuate MG132 mediated decrease in proteasome and calpain activities. In vitro findings revealed that SFN could induce proteasomal activity by enhancing the expression of catalytic subunit-β5. SFN pre-administration prevented the hippocampus based spatial memory impairments during adulthood, mediated by postnatal MG132 exposure. Histological examination showed deleterious effects of MG132 on pyramidal neurons and granule cell neurons in DG and CA3 sub-regions respectively. Furthermore, SFN pre-administration has shown to attenuate the effect of MG132 on proteasome subunit-β5 expression and also induce the Nrf2 nuclear translocation. In addition, SFN pre-administered mice have also shown to induce expression of pCaMKII, pCreb, and mature/pro-Bdnf, molecules which play a crucial role in spatial learning and memory consolidation. Our findings have shown that proteasomes play an important role in hippocampal synaptic plasticity during the early postnatal period and SFN pre-administration could enhance the proteasomal activity as well as improve spatial learning and memory consolidation.

Topics: Animals; Animals, Newborn; CA3 Region, Hippocampal; Cell Line, Tumor; Dentate Gyrus; Gene Expression Regulation, Developmental; Hippocampus; Humans; Injections, Intraventricular; Isothiocyanates; Leupeptins; Memory Disorders; Mice, Inbred BALB C; Nerve Tissue Proteins; Neuronal Plasticity; Neurons; Neuroprotective Agents; Neurotoxicity Syndromes; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Pyramidal Cells; Spatial Learning; Sulfoxides

Effects of a protease inhibitor, leupeptin, on the memory function and the morphological changes in the hippocampus were examined in rats. The leupeptin was infused by an implanted-osmotic minipump into the lateral ventricle of the rats for 14 days. The acquisition and the maintenance of memory were evaluated by a step-down passive avoidance task. The control rats, infused with an artificial cerebral spinal fluid, showed good retention for the passive avoidance training for 21 days after training. The leupeptin-treated rats showed good retention for 7 days following training; however, pronounced impaired retention was observed on day 10 and thereafter. These rats were accompanied by a degeneration of the dentate gyrus in the histological examinations on Days 14 and 21. The granule cells in the dentate gyrus of the hippocampus appeared much more eosinophilic pyknotic. Numerous eosinophilic spherical structures of the cell processes were seen in the neuropil beneath the granule cell layer. Electron microscopic examination disclosed a marked accumulation of lipofuscin-like granules in the perikaryon of the cells and in the dendrites and the axons. These findings suggest that the memory impairment is closely related to the degeneration of the dentate gyrus in the hippocampus in the leupeptin-treated rats.

Topics: Animals; Avoidance Learning; Axons; Cerebral Ventricles; Cytoplasmic Granules; Dendrites; Dentate Gyrus; Hippocampus; Infusions, Parenteral; Leupeptins; Lipofuscin; Memory; Memory Disorders; Motor Activity; Nerve Degeneration; Neurons; Rats; Rats, Wistar