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Brain. 2017 Dec 1;140(12):3269-3285. doi: 10.1093/brain/awx256.

Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons.

Author information

Karolinska Institutet, Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Stockholm, Sweden.
Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Spain.
Fundación CIEN, Madrid, Spain.
Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, Spain.
Institut de Neuropatologia, Servei Anatomia Patologica, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat, Barcelona, Spain.


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.


Alzheimer’s disease; insulin; neurofibrillary tangles; oligomers; tau

[Indexed for MEDLINE]

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