Journal
BRAIN
Volume 140, Issue -, Pages 3269-3285Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awx256
Keywords
insulin; tau; oligomers; Alzheimer's disease; neurofibrillary tangles
Categories
Funding
- PHS grant [R24MHO68855]
- EMBO [ALFT 6962013]
- SSMF postdoctoral fellowship
- Swedish Brain Power
- Stockholm County Council
- Karolinska Institutet
- Margaretha af Ugglas Foundation
- Olle Engkvist Byggmastare Stiftelse
- Gun och Bertil Stohnes Stiftelse
- Loo och Hans Osterman Foundation
- Karolinska Institutet fund for geriatric research
- Stiftelsen Gamla Tjanarinnor
- Riskbankens Jubileumfonden
- Hjarnfonden
- Alzheimerfonden
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Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications.
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