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Targeting Tau Protein in Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is characterized histopathologically by numerous neurons with neurofibrillary tangles and neuritic (senile) amyloid-β (Aβ) plaques, and clinically by progressive dementia. Although Aβ is the primary trigger of AD according to the amyloid cascade hypothesis, neurofibrillary degeneration of abnormally hyperphosphorylated tau is apparently required for the clinical expression of this disease. Furthermore, while approximately 30% of normal aged individuals have as much compact plaque burden in the neocortex as is seen in typical cases of AD, in several tauopathies, such as cortical basal degeneration and Pick’s disease, neurofibrillary degeneration of abnormally hyperphosphorylated tau in the absence of Aβ plaques is associated with dementia. To date, all AD clinical trials based on Aβ as a therapeutic target have failed. In addition to the clinical pathological correlation of neurofibrillary degeneration with dementia in AD and related tauopathies, increasing evidence from in vitro and in vivo studies in experimental animal models provides a compelling case for this lesion as a promising therapeutic target. A number of rational approaches to inhibiting neurofibrillary degeneration include inhibition of one or more tau protein kinases, such as glycogen synthase kinase-3β and cyclin-dependent protein kinase 5, activation of the major tau phosphatase protein phosphatase-2A, elevation of β-N-acetyl-glucosamine modification of tau through inhibition of β-N-acetylglucosaminidase or increase in brain glucose uptake, and promotion of the clearance of the abnormally hyperphosphorylated tau by autophagy or the ubiquitin proteasome system.

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Acknowledgements

Studies carried out in our laboratories were supported in part by the New York State Office of Mental Retardation and Developmental Disabilities and National Institutes of Health grants AG019158, AG028538, AG27429, AG031969 and TW008123. The authors have no conflicts of interest that are directly relevant to the content of this article. The authors are grateful to Janet Murphy for secretarial assistance.

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  1. Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York, 10314, USA

    Cheng-Xin Gong, Inge Grundke-Iqbal &  Khalid Iqbal

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  1. Cheng-Xin Gong
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Correspondence to Khalid Iqbal.

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Gong, CX., Grundke-Iqbal, I. & Iqbal, K. Targeting Tau Protein in Alzheimer’s Disease. Drugs Aging 27, 351–365 (2010). https://doi.org/10.2165/11536110-000000000-00000

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