University of Auckland, New Zealand
Ji Zhong Bai is a Biomedical Researcher working in the Faculty of Medical and Health Sciences at the University of Auckland, New Zealand. He graduated from the Shanxi Normal University in China, and obtained his Postgraduate Diploma training in Biochemistry from Wuhan University in China in 1988. He received an MSc degree in Biochemistry with First Class Honours from the University of Auckland in New Zealand in 1994, where he also completed his PhD in Biological Sciences in 1999. Since then, he has been working as a Postdoctoral and Research Fellow in the School of Medical Sciences at the University of Auckland. He has extensive research experience in the fields of Cell biology/physiology, Molecular neurobiology and biomedical imaging, with particularly tissue culture techniques of organotypic brain slice and primary cells. He has published widely in peer reviewed journals and serving as referee for several international journals of neurological sciences.
Brain accumulation of toxic amyloid β (Aβ) species is widely accepted as the primary factor in the pathogenesis of Alzheimer’s disease (AD). Studies also suggest that Aβ-induced oxidative stress and deficient calcium homeostasis play a major role in the progression towards neuronal death.However,the mechanism of these effects is still not well understood. We have recently demonstrated that Ca2+-permeable TRPV4 channels are highly expressed in rat hippocampal astrocytes and are involved in oxidative stress-induced cell damage. The aim of this study was to examine the potential role of TRPV4channels in Aβ-evoked damage of the hippocampus, a brain region highly vulnerable in AD. In hippocampal slice cultures preconditioned with sublethal concentration of buthioninesulfoximine (BSO;1.5 µM) to enhance endogenous ROS production by inhibiting glutathione synthesis, synthetic Aβ40 mainly damaged neurons in the dental gyrus (DG) and pyramidal CA1-CA3 region, as shown by propidium iodide (PI) fluorescence. Astrocytes were damaged to a smaller degree, mainly at the edge of the slice. Immunocytochemistry revealed an altered pattern of TRPV4 and GFAP protein expression, andreactive astrogliosis surrounding pyramidal CA1-CA3 neurons. In contrast, endogenous increase of H2O2/ROS induced by a higher concentration of BSO (4 M) predominately evoked damage of TRPV4-expressing astrocytes in the form of large ‘patches’ of PI fluorescence mainly around DG, while CA1/CA3 hippocampal neurons were less affected. Astrocytic and neuronal death induced by A40or 4MBSO was attenuated by the antioxidant Trolox, TRPV4 channel blockers Gd3+ and ruthenium red (RR).Aβ40-evoked hippocampal damage was also blocked by a specific inhibitor of the redox and Ca2+-sensitive phospholipase A2 enzyme (MAFP). In disassociated co-cultures of hippocampal neurons and astrocytes, Aβ40 evoked pronounced neuronal damage,enhanced the expression of TRPV4 and GFAP proteins, and increased intracellular free Ca2+ concentration in astrocytes. The latter effect was attenuated by RR and in Ca2+-free media. These data indicate that TRPV4-expressing astrocytes protecthippocampal pyramidal neurons against oxidative damage, and that Aprimarily activates astrocytic TRPV4 channels in the hippocampus leading to neuronal death with only limited astrocytic damage, in a Ca2+ and oxidative stress-dependent manner.We propose that the altered astrocytic state affects neuronal survival due to lack of trophic and other support, forming a link between astrocyte dysfunction and neurodegeneration in AD.
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