Effects Of Coenzyme Q10 On Increased β-amyloid And Tau Hyperphosphorylation In The Aged Transgenic Mice With Alzheimer Presenilin 1 Mutation

Alzheimer's disease is characterized byβ-amyloid (Aβ) overproduction and tau hyperphosphorylation. The underlying mechanisms linking Aβand aberrant tau phosphorylation are poorly understood, and therefore there are no effective therapeutic measures for arresting the AD pathology. In our present study, we found that familial Alzheimer disease mutation with presenilin 1-L235P(leucine-to-proline mutation at codon 235 ) transgenic mice (PS-1 Tg) enhanced the generation of Aβ42, and significantly increased intracellular Aβ42 deposition in the brain of the aged Tg mice (16-17 months old). We also determined the alterations of phosphorylated tau and found that phosphorylation of tau at pSer396, Tau-1 (Ser198/199/202) and pSer404 epitopes was significantly increased in the aged Tg mice compared with the age-matched wild type mice (WT). Meanwhile, we detected an increased oxidative stress reaction as evidenced by elevated level of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) in the aged Tg mice, compared to the WT mice. We further detected the alterations in Akt-GSK-3βsignaling pathway and found a decreased phosphorylation of Akt, glycogen synthase kinase (GSK)-3βin the aged Tg mice. Exogenous supplementation of coenzyme Q10 (CoQ10), a powerful antioxidant and free radical scavenger, not only partially decreased MDA level and up-regulated the activity of SOD, but also arrested Aβ42 level and tau hyperphosphorylation, concurrently accompanied with a restoration of Akt-GSK-3βsignaling. These results suggest that the mutated PS-1 increases Aβ42 production and intracellular deposition selectively and tau hyperphosphorylation. The latter may be a consequence of intracellular overproduced Aβinduced-oxidative stress and the mechanisms may involve depression of oxidative stress-induced Akt-GSK-3βsignaling events. The neuroprotective effects of CoQ10 may act through its antioxidant property. Our data also indicate that the pathogenic role of the mutated PS-1 is upstream of the amyloid cascade and taupathy, and CoQ10 might be potentially useful for therapy of Alzheimer's disease.Part twoMelatonin Meliorates Calyculin A-induced Axonal Transport Defects and Spatial Memory Retention Impairment in RatsWe have recently found that melatonin protects SH-SY5Y neuroblastoma cells from calyculin A(CA)-induced neurofilament impairment and neurotoxicity. In the present study, we further investigated the in vivo effect of melatonin on spatial memory retention in rats by bilateral injection of CA, a potent and specific inhibitor of protein phosphatase-2A (PP-2A) and protein phosphatase-1 (PP-1) into hippocampus. We found that the supplementation of melatonin by intraperitoneal injection for 9 days before injecting CA not only significantly improves CA-induced memory retention deficits of the rats in the Morris Water-Maze Test, but also decreases hyperphosphorylation of neuronal cytoskeletal protein tau and neurofilaments. To further explore the underlying mechanisms of the protective effect of melatonin on spatial memory deficit in rats induced by CA, we analyzed the axonal transport by a time-lapse recording of pEGFP-labeled neurofilament-M (pEGFP-NF-M) subunit in live neuroblastoma N2a cells and found that melatonin partially reversed CA-induced impairment of transport of pEGFP- NF-M in the axon-like processes of the cells. In the meantime, we found by western blot that melatonin also decreased CA-induced hyperphosphorylation of cytoskeletal proteins. In addition, we explored the effect of melatonin on the morphological alteration of the cells during inhibition of the phosphatases by establishing 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, and the administration of melatonin significantly arrested these pathological alterations. These data suggest that melatonin not only meliorated impaired intracellular transport induced by suppression of PP-2A and PP-1, but also cell degeneration, which may underlie the basis of the effects of protection of melatonin on memory deficits induced by suppression of the phosphatases.