Rho-associated kinases contribute to the regulation of tau phosphorylation and amyloid metabolism during neuronal plasticity.

BACKGROUND: Neural plasticity under physiological condition develops together with normal tau phosphorylation and amyloid precursor protein (APP) processing. Since restoration of PI3-kinase signaling has therapeutic potential in Alzheimer's disease, we investigated plasticity-related changes in tau and APP metabolism by the selective Rho-kinase inhibitor fasudil. METHODS: Field potentials composed of a field excitatory post-synaptic potential (fEPSP) and a population spike (PS) were recorded from a granule cell layer of the dentate gyrus. Plasticity of synaptic strength and neuronal function was induced by strong tetanic stimulation (HFS) and low-frequency stimulation (LFS) patterns. Infusions of saline or fasudil were given for 1 h starting from the application of the induction protocols. Total and phosphorylated tau levels and soluble APPα levels were measured in the hippocampus, which was removed after at least 1 h post-induction period. RESULTS: Fasudil infusion resulted in attenuation of fEPSP slope and PS amplitude in response to both HFS and LFS. Fasudil reduced total tau and phosphorylated tau at residue Thr181 in the HFS-stimulated hippocampus, while Thr231 phosphorylation was reduced by fasudil treatment in the LFS-stimulated hippocampus. Ser416 phosphorylation was increased by fasudil treatment in both HFS- and LFS-stimulated hippocampus. Fasudil significantly increased soluble APPα in LFS-stimulated hippocampus, but not in HFS-stimulated hippocampus. CONCLUSION: In light of our findings, we suggest that increased activity of Rho kinase could trigger a mechanism that goes awry during synaptic plasticity which is reversed by a Rho-kinase inhibitor. Thus, Rho-kinase inhibition might be a therapeutic target in cognitive disorders.

Age-dependent evaluation of long-term depression responses in hyperthyroid rats: Possible roles of oxidative intracellular redox status.

BACKGROUND: According to the free radical theory, a gradual accumulation of the free radicals normally produced in the body underlies the changes associated with aging. Thyroid hormones (THs) are related to oxidative stress not only due to their stimulation of metabolism but also due to their effects on antioxidant mechanisms. Thyroid dysfunction increases with age; thus, changes in TH levels in elderly individuals could be a factor affecting the development of neurodegenerative diseases. However, the relationship is not always clear, based on current evidence regarding synaptic plasticity. METHODS: Hippocampal long-term depression (LTD) and oxidative status in the hippocampus were evaluated at two different ages (2-3 and 12-14 months) in male rats. Rats were administered 0.2 mg/kg/day of l-thyroxine for 21 days starting at postnatal day 40 to induce hyperthyroidism. LTD was induced in the dentate gyrus using low frequency stimulation of the perforant pathway. Spectrophotometry was performed to measure catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) levels, glutathione peroxidase (GPx) activity, and total nitrite/nitrate (tNOx) and nitric oxide synthase (NOS) levels. RESULTS: A reliable LTD was elicited in young rats with hyperthyroidism, while the same protocol could induce a small magnitude of synaptic LTD in the absence of spike-LTD in control rats. In aged rats, controls did not express LTD, but a significant LTP of spike was induced in the absence of synaptic LTD in hyperthyroid rats. While CAT levels were significantly decreased, MDA levels were increased in the aged groups compared to the corresponding young groups. Young rats with euthyroidism had significantly lower GPx activity than each of the hyperthyroid groups. There was no significant difference in SOD levels among the groups. Compared with aged rats, young rats exhibited a hyperthyroidism-induced decrease in NOS levels. Nevertheless, neither the main effects of age and thyroxine administration nor the interaction between these factors reached significance for tNOx. CONCLUSION: These results indicate that hyperthyroidism-related changes in synaptic plasticity are modulated by aging. This modulation may explain the increased cognitive impairment in this disease at older ages, which probably depends on alterations in NOS levels.