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AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer's disease and other tauopathies.
Acta Neuropathol 2011; 121(3):337-49AN

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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

20957377

Citation

Vingtdeux, Valérie, et al. "AMPK Is Abnormally Activated in Tangle- and Pre-tangle-bearing Neurons in Alzheimer's Disease and Other Tauopathies." Acta Neuropathologica, vol. 121, no. 3, 2011, pp. 337-49.
Vingtdeux V, Davies P, Dickson DW, et al. AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer's disease and other tauopathies. Acta Neuropathol. 2011;121(3):337-49.
Vingtdeux, V., Davies, P., Dickson, D. W., & Marambaud, P. (2011). AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer's disease and other tauopathies. Acta Neuropathologica, 121(3), pp. 337-49. doi:10.1007/s00401-010-0759-x.
Vingtdeux V, et al. AMPK Is Abnormally Activated in Tangle- and Pre-tangle-bearing Neurons in Alzheimer's Disease and Other Tauopathies. Acta Neuropathol. 2011;121(3):337-49. PubMed PMID: 20957377.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2010/10/19/ PY - 2010/09/01/received PY - 2010/10/06/accepted PY - 2010/10/05/revised PY - 2010/10/20/entrez PY - 2010/10/20/pubmed PY - 2011/6/15/medline SP - 337 EP - 49 JF - Acta neuropathologica JO - Acta Neuropathol. VL - 121 IS - 3 N2 - 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. SN - 1432-0533 UR - https://www.unboundmedicine.com/medline/citation/20957377/AMPK_is_abnormally_activated_in_tangle__and_pre_tangle_bearing_neurons_in_Alzheimer's_disease_and_other_tauopathies_ L2 - https://dx.doi.org/10.1007/s00401-010-0759-x DB - PRIME DP - Unbound Medicine ER -