Abstract
Alzheimer disease (AD) is the most common cause of dementia in adults. The current therapy for AD has only moderate efficacy in controlling symptoms, and it does not cure the disease. Recent studies have suggested that abnormal hyperphosphorylation of tau in the brain plays a vital role in the molecular pathogenesis of AD and in neurodegeneration. This article reviews the current advances in understanding of tau protein, regulation of tau phosphorylation, and the role of its abnormal hyperphosphorylation in neurofibrillary degeneration. Furthermore, several therapeutic strategies for treating AD on the basis of the important role of tau hyperphosphorylation in the pathogenesis of the disease are described. These strategies include (1) inhibition of glycogen synthase kinase-3β (GSK-3β), cyclin-dependent kinase 5 (cdk5), and other tau kinases; (2) restoration of PP2A activity; and (3) targeting tau O-GlcNAcylation. Development of drugs on the basis of these strategies is likely to lead to disease-modifying therapies for AD.
Highlights
Alzheimer disease (AD) is a chronic neurodegenerative disease that is characterized clinically by a progressive decline of cognitive function, leading to dementia
In wild-type mice, peripheral administration of STZ led to increased tau phosphorylation at various sites, but did not lead to the formation of insoluble aggregates
Anesthesia-induced hypothermia results in increases in tau phosphorylation through the inhibition of phosphatase activity
Summary
Alzheimer disease (AD) is a chronic neurodegenerative disease that is characterized clinically by a progressive decline of cognitive function, leading to dementia. More and more evidence has demonstrated a crucial role of tau abnormalities in AD neurodegeneration, suggesting that tau could be a promising therapeutic target for developing disease-modifying drugs of AD. Tau Mutations Found in Frontotemporal Dementia Promote Abnormal Hyperphosphorylation
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