TY - JOUR
T1 - AMPK is abnormally activated in tangle-and pre-tangle-bearing neurons in Alzheimer's disease and other tauopathies
AU - Vingtdeux, Valérie
AU - Davies, Peter
AU - Dickson, Dennis W.
AU - Marambaud, Philippe
N1 - Funding Information:
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.).
PY - 2011/3
Y1 - 2011/3
N2 - Tauopathies represent a class of neurode-generative 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 immu-noreactivity 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.
AB - Tauopathies represent a class of neurode-generative 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 immu-noreactivity 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.
KW - AMPK
KW - Alzheimer's disease
KW - Tangles
KW - Tau
KW - Tauopathies
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U2 - 10.1007/s00401-010-0759-x
DO - 10.1007/s00401-010-0759-x
M3 - Article
C2 - 20957377
AN - SCOPUS:79952135316
SN - 0001-6322
VL - 121
SP - 337
EP - 349
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 3
ER -