calyculin-a and Memory-Disorders

We have reported recently that inhibition of protein phosphatase (PP)-2A and PP-1 by calyculin A, a specific inhibitor of PP-2A and PP-1, induced Alzheimer-like hyperphosphorylation of tau and spatial memory retention impairment. In this study, we tested the in vivo effects of melatonin on these Alzheimer-like changes. We found that administration of melatonin intraperitoneally for 9 consecutive days before injection of calyculin A could prevent calyculin A-induced synaptophysin loss, memory retention deficits, as well as hyperphosphorylation of tau and neurofilaments. Furthermore, melatonin partially reversed the phosphorylation of the catalytic subunit of PP-2A at Tyrosine 307 (Y307), a crucial site negatively regulating the activity of PP-2A, and reduced the levels of malondialdehyde, a marker of oxidative stress, induced by calyculin A. These results suggest that melatonin could serve as a potential therapeutic agent for preventing Alzheimer-like pathological changes and behavioral abnormality via modulating the activity of PP-2A and oxidative stress.

Topics: Alzheimer Disease; Animals; Antioxidants; Behavior, Animal; Disease Models, Animal; Male; Malondialdehyde; Marine Toxins; Melatonin; Memory Disorders; Oxazoles; Oxidative Stress; Phosphorylation; Protein Phosphatase 2; Rats; Rats, Sprague-Dawley; tau Proteins

The activity of protein phosphatase (PP)-2A and PP-1 decreased in the brains of Alzheimer's disease and inhibition of the phosphatases led to spatial memory deficit in rats. However, the molecular basis underlying memory impairment of the phosphatase inhibition is elusive. In the present study, we observed a selective inhibition of PP-2A and PP-1 with Calyculin A (CA) not only caused hyperphosphorylation of cytoskeletal proteins, but also impaired the transport of pEGFP-labeled neurofilament-M subunit in the axon-like processes of neuroblastoma N2a cells and resulted in accumulation of neurofilament in the cell bodies. To analyze the morphological alteration of the cells during inhibition of the phosphatases, we established a cell model showing steady outgrowth of axon-like cell processes and employed a stereological system to analyze the retraction of the processes. We found CA treatment inhibited outgrowth of the cell processes and prolonged treatment with CA caused retraction of the processes and meanwhile, the early neurodegenerative varicosities were also obvious in the CA-treated cells. We conclude suppression of PP-2A and PP-1 by CA not only damages intracellular transport but also leads to cell degeneration, which may serve as the functional and structural elements for the memory deficits induced by suppression of the phosphatases.

Topics: Animals; Axonal Transport; Axons; Brain; Cell Differentiation; Cell Line, Tumor; Enzyme Inhibitors; Image Cytometry; Marine Toxins; Memory Disorders; Mice; Nerve Degeneration; Neurites; Neurofilament Proteins; Oxazoles; Phosphoprotein Phosphatases