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AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies

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Abstract

Tauopathies represent a class of neurodegenerative disorders characterized by abnormal tau phosphorylation and aggregation into neuronal paired helical filaments (PHFs) and neurofibrillary tangles. AMP-activated protein kinase (AMPK) is a metabolic sensor expressed in most mammalian cell types. In the brain, AMPK controls neuronal maintenance and is overactivated during metabolic stress. Here, we show that activated AMPK (p-AMPK) is abnormally accumulated in cerebral neurons in 3R+4R and 3R tauopathies, such as Alzheimer’s disease (AD), tangle-predominant dementia, Guam Parkinson dementia complex, Pick’s disease, and frontotemporal dementia with parkinsonism linked to chromosome 17, and to a lesser extent in some neuronal and glial populations in the 4R tauopathies, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease. In AD brains, p-AMPK accumulation decorated neuropil threads and dystrophic neurites surrounding amyloid plaques, and appeared in more than 90% of neurons bearing pre-tangles and tangles. Granular p-AMPK immunoreactivity was also observed in several tauopathies in apparently unaffected neurons devoid of tau inclusion, suggesting that AMPK activation preceded tau accumulation. Less p-AMPK pathology was observed in PSP and CBD, where minimal p-AMPK accumulation was also found in tangle-positive glial cells. p-AMPK was not found in purified PHFs, indicating that p-AMPK did not co-aggregate with tau in tangles. Finally, in vitro assays showed that AMPK can directly phosphorylate tau at Thr-231 and Ser-396/404. Thus, activated AMPK abnormally accumulated in tangle- and pre-tangle-bearing neurons in all major tauopathies. By controlling tau phosphorylation, AMPK might regulate neurodegeneration and therefore could represent a novel common determinant in tauopathies.

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Acknowledgments

We thank Dr. K. R. Laderoute (SRI International, Menlo Park, CA) for kindly providing us with α1/2AMPK null fibroblasts, and Dr. A. Chan and S. Didier (The Feinstein Institute for Medical Research, Manhasset, NY) for assistance with microscopy analyses. This work was supported in part by the Institutional Clinical and Translational Science Award UL1-RR024996 (Weill Medical College of Cornell University, New York, NY, USA; CTSC Pilot Award, to P. M.) and National Institutes of Health Grant PO1 AT004511 (NCCAM Project 2, to P. M.).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Litwin-Zucker Research Center for the Study of Alzheimer’s Disease, The Feinstein Institute for Medical Research, North Shore-LIJ, 350 Community Drive, Manhasset, NY, 11030, USA

    Valérie Vingtdeux, Peter Davies & Philippe Marambaud

  2. Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Peter Davies & Philippe Marambaud

  3. Neuropathology Laboratory, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Dennis W. Dickson

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  1. Valérie Vingtdeux
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Correspondence to Philippe Marambaud.

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Vingtdeux, V., Davies, P., Dickson, D.W. et al. AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies. Acta Neuropathol 121, 337–349 (2011). https://doi.org/10.1007/s00401-010-0759-x

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