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

Valérie Vingtdeux, Peter Davies, Dennis W Dickson, Philippe Marambaud

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)337-349
Number of pages13
JournalActa Neuropathologica
Volume121
Issue number3
DOIs
StatePublished - Mar 2011

Fingerprint

Tauopathies
AMP-Activated Protein Kinases
Alzheimer Disease
Neurons
Progressive Supranuclear Palsy
Neuroglia
Dementia
Neuropil Threads
Guam
Phosphorylation
Pick Disease of the Brain
Frontotemporal Dementia
Chromosomes, Human, Pair 17
Neurofibrillary Tangles
Physiological Stress
Amyloid Plaques
Brain
Neurites

Keywords

  • Alzheimer's disease
  • AMPK
  • Tangles
  • Tau
  • Tauopathies

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

AMPK is abnormally activated in tangle-and pre-tangle-bearing neurons in Alzheimer's disease and other tauopathies. / Vingtdeux, Valérie; Davies, Peter; Dickson, Dennis W; Marambaud, Philippe.

In: Acta Neuropathologica, Vol. 121, No. 3, 03.2011, p. 337-349.

Research output: Contribution to journalArticle

Vingtdeux, Valérie ; Davies, Peter ; Dickson, Dennis W ; Marambaud, Philippe. / AMPK is abnormally activated in tangle-and pre-tangle-bearing neurons in Alzheimer's disease and other tauopathies. In: Acta Neuropathologica. 2011 ; Vol. 121, No. 3. pp. 337-349.
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