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2005 Grant - Zhu
Physiological Regulation of Tau Phosphorylation
Xiongwei Zhu, Ph.D.
Case Western Reserve University,
2005 New Investigator Research Grant
One of the hallmarks of Alzheimer's disease is the neurofibrillary tangle. This is a dense clump, or aggregate, of proteins comprised mainly of an abnormally altered protein called tau.
Tau plays a crucial role in maintaining the structural framework and transport system within nerve cells. While tau is normally modified by the attachment of phosphate molecules, a process called phosphorylation, excessive phos-phorylation appears to contribute to tangle formation and prevents the protein from carrying out its normal functions.
Studies have shown that the extent of tau phosphorylation is closely related to the severity of Alzheimer's disease. This suggests that the ability to reverse tau phosphorylation could be of therapeutic benefit. However, studying tau phosphorylation in live animals has proven particularly challenging.
Xiongwei Zhu, Ph.D., and colleagues will examine the role of tau phosphory-lation in a unique physiological settingóthe arctic ground squirrel. Recently Zhu and colleagues discovered that during hibernation, brain activity in this animal is dramatically reduced. This loss of neural activity is also accom-panied by greatly increased phosphorylation of tau. Remarkably, this tau modification occurs in some of the same brain regions where neurofibrillary tangles are formed during Alzheimer's disease. Perhaps more importantly, when these animals come out of hibernation, tau returns to normal. These findings suggest that there may be a mechanism by which tau phosphorylation may be therapeutically reversed in the Alzheimer brain.
To better understand the processes governing the modification of tau, the researchers will examine what factors contributing to phosphorylation and
the reverse, "de-phosphorylation," of the protein as arctic squirrels enter and exit hibernation. The findings could pinpoint molecules that play a crucial role in the formation of neurofibrillary tangles in humans and suggest new therapeutic strategies.