Neuroprotective Role of DING Protein in Normal Aging and Alzheimer's Disease

Previously, we showed that the phosphatase DING extracted from St. John's wort (p38SJ) is neuroprotective against EtOH-mediated toxicity in rat and human fetal neurons in vitro. Now, we assess the role of human DING in Alzheimer's disease (AD). DING (p38SJ/p38hu), a member of the DING family of proteins, has been shown to be neuroprotective against cellular stress injury induced by alcohol, HIV-1, and in cancer cells. DING has demonstrated phosphatase activity on MAPK substrates, but its effect on Tau phosphorylation, which is involved in AD, has not yet been explored.

Expression of DING protein levels was studied in human postmortem brain using histochemistry and quantitative western blot with ANOVA. Five patients with dementia, of whom 3 had AD neuropathology, a fourth had AD/Parkinson complex, and one had cerebrovascular dementia, were compared with 5 non-dementia controls.

DING was present in the neuronal cell bodies and processes of both normal and AD-affected human brain tissue. DING demonstrated phosphatase activity in PC12 cells (a cell line derived from rat pheochromocytoma) and inhibited Tau phosphorylation in these cells and in human brain tissue (both normal and AD). Increasing DING by transduction and overexpression in PC12 cells was associated with increased cell survival. In human brains (age=72-92 years), levels of endogenously expressed 38 kDa DING protein correlated positively with Tau dephosphorylation.

Excess Tau phosphorylation leads to the formation of neurofibrillary tangles in neurons, a hallmark of neurodegeneration in Alzheimer's disease. DING inhibits Tau phosphorylation and increases cell viability in non-proliferating neuronal cells overexpressing Tau, while reducing the viability of proliferating cells. Thus, DING may be neuroprotective in AD.