Yinghe Hu

In addition to senile plaques and cerebral amyloid angiopathy, the hyperphosphorylation of tau protein and formation of intraneuronal neurofibrillary tangles (NFTs) represents another neuropathological hallmark in AD brain. Tau is a microtubule-associated protein and localizes predominantly in the axons of neurons with the primary function in maintaining microtubules stability. When the balance between tau phosphorylation and dephosphorylation is changed in favor of the former, tau is hyperphosphorylated and the level of the free tau fractions elevated. The hyperphosphorylation of tau protein and formation of NFTs represent a characteristic neuropathological feature in AD brain. We have discussed the role of Aβ in AD in our previous review, this review focused on the recent advances in tau-mediated AD pathology, mainly including tau hyperphosphorylation, propagation of tau pathology and the relationship between tau and Aβ.

Alzheimer’s disease (AD) is a common neurodegenerative disease characterized clinically by progressive deterioration of memory, and pathologically by histopathological changes including extracellular deposits of amyloid-beta (A-beta) peptides forming senile plaques (SP) and the intracellular neurofibrillary tangles (NFT) of hyperphosphorylated tau in the brain. This review focused on the new developments of amyloid cascade hypothesis with details on the production, metabolism and clearance of A-beta, and the key roles of some important A-beta-related genes in the pathological processes of AD. The most recent research advances in genetics, neuropathology and pathogenesis of the disease were also discussed.

GPR12, a member of the orphan G-protein-coupled receptor family, constitutively activates the Gs protein and increases intracellular cyclic AMP concentrations. GPR12 can be activated by its known ligand—sphingosylphosphorylcholine, which regulates cellular physiological activities, including proliferation, neurite extension, cell clustering, and maintenance of meiotic arrest. However, signaling pathways involved in the GPR12-mediated physiological and biochemical changes are still not clearly illustrated. In the present study, heterologous GPR12 expression was demonstrated to promote proliferation and survival in human embryonic kidney 293 cells. Immunochemical analysis showed that Ki67, a prototypic cell cycle-related nuclear protein, might participate in the regulation of GPR12-mediated cell proliferation. Activation of extracellular signal-regulated protein kinase signaling and increased total Erk1/2 and B-cell lymphoma/leukemia-2 expression were also observed in HEK293 cells overexpressing human GPR12. In addition, we found that GPR12 promoted cell survival under serum deprivation, indicating that GPR12 may play a role in cell proliferation and survival.

Background: The G-protein-coupled receptor (GPCR) superfamily represents the largest protein family in the human genome. These proteins have a variety of physiological functions that give them well recognized roles in clinical medicine. InXenopus tropicalis, a widely used animal model for physiology research, the repertoire of GPCRs may help link the GPCR evolutionary history in vertebrates from teleost fish to mammals.Results: We have identified 1452 GPCRs in theX. tropicalisgenome. Phylogenetic analyses classified these receptors into the following seven families:Glutamate,Rhodopsin,Adhesion,Frizzled,Secretin,Taste 2andVomeronasal 1. Nearly 70% ofX. tropicalisGPCRs are represented by the following three types of receptors thought to receive chemosensory information from the outside world: olfactory, vomeronasal 1 and vomeronasal 2 receptors.Conclusion: X. tropicalisshares a more similar repertoire of GPCRs with mammals than it does with fish. An examination of the three major groups of receptors related to olfactory/pheromone detection shows that inX. tropicalis, these groups have undergone lineage specific expansion. A comparison of GPCRs inX. tropicalis, teleost fish and mammals reveals the GPCR evolutionary history in vertebrates.

We have investigated the effects of lysophosphatidylcholine (LPC), a product of lipid peroxidation, on Aβ_1–42-induced SH-SY5Y cell apoptosis. The viability of cultured SH-SY5Y cells was measured using a CCK-8 kit. Apoptosis was determined by Chip-based flow cytometric assay. The mRNA transcription of Bcl-2, Bax, and caspase-3 were detected by using reverse transcription and real-time quantitative PCR and the protein levels of Bax and caspase-3 were analyzed by Western blotting. The cytosolic calcium concentration of SH-SY5Y cells was tested by calcium influx assay. G2A expression in SH-SY5Y cells was silenced by small interfering RNA. Long-term exposure of SH-SY5Y cells to LPC augmented the neurotoxicity of Aβ_1–42. Furthermore, after LPC treatment, the Bax/Bcl-x_L ratio and the expression levels, as well as the activity of caspase-3 were, elevated, whereas the expression level of TRAF1 was reduced. Because LPC was reported to be a specific ligand for the orphan G-protein coupled receptor, G2A, we investigated LPC-mediated changes in calcium levels in SH-SY5Y cells. Our results demonstrated that LPC can enhance the Aβ_1–42-induced elevation of intracellular calcium. Interestingly, Aβ_1–42 significantly increased the expression of G2A in SH-SY5Y cells, whereas knockdown of G2A using siRNA reduced the effects of LPC on Aβ_1–42-induced neurotoxicity. The effects of LPC on Aβ_1–42-induced apoptosis may occur through the signal pathways of the orphan G-protein coupled receptor.

A transgenic mouse model expressing Simian virus 40 T‐antigen (SV40Tag) under the control of a tetracycline system was generated. In this model, a cerebellar tumor was developed after doxycycline hydrochloride treatment. Real time‐polymerase chain reaction and immunohistochemistry results indicated that the SV40Tag gene was expressed in the tumor. Pathological analysis showed that the tumor belonged to medulloblastoma. Further molecular characterization of the tumor demonstrated that the insulin‐like growth factor (IGF) signaling pathway was activated. We also found that the SV40Tag could bind and translocate insulin receptor substrate 1 into the nucleus in primary cultured tumor cells. The interaction between the IGF pathway and SV40Tag may contribute to the process of malignant transformation in medulloblastoma. This transgenic animal model provides an important tool for studies on the signal pathways involved in the preneoplastic process in medulloblastoma and could help to identify therapeutic targets for brain tumors. (Cancer Sci 2008; 99: 234–240)

Presenilin (PS) 1 and 2 conditional double knockout (cDKO) mice show progressive memory dysfunction and forebrain degeneration. Gene expression profiling results revealed a strong activation of immunity and inflammation responses in the brains of 10‐month‐old cDKO mice. As environmental enrichment (EE) has been shown to be able to improve memory and induce neurogenesis of the brain, we assessed the effects of EE on the memory performance and the neurodegeneration in cDKO mice. We found that EE effectively enhanced memory and partially rescued the forebrain atrophy of the cDKO mice. Our results suggest that immunity and inflammation could play important roles in the neurodegeneration of cDKO mice. Furthermore, the beneficial effects of EE may be associated with the inhibition of the expression of immunity and inflammation‐related genes in the brain.