Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degenerationReport as inadecuate

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Acta Neuropathologica

, Volume 132, Issue 6, pp 897–916

First Online: 14 October 2016Received: 28 July 2016Revised: 05 October 2016Accepted: 05 October 2016


The role of microglial cells in the development and progression of Alzheimer’s disease AD has not been elucidated. Here, we demonstrated the existence of a weak microglial response in human AD hippocampus which is in contrast to the massive microglial activation observed in APP-based models. Most importantly, microglial cells displayed a prominent degenerative profile dentate gyrus > CA3 > CA1 > parahippocampal gyrus, including fragmented and dystrophic processes with spheroids, a reduced numerical density, and a significant decrease in the area of surveillance -microglial domain-. Consequently, there was a substantial decline in the area covered by microglia which may compromise immune protection and, therefore, neuronal survival. In vitro experiments demonstrated that soluble fractions extracellular-cytosolic from AD hippocampi were toxic for microglial cells. This toxicity was abolished by AT8 and-or AT100 immunodepletion, validating that soluble phospho-tau was the toxic agent. These results were reproduced using soluble fractions from phospho-tau-positive Thy-tau22 hippocampi. Cultured microglial cells were not viable following phagocytosis of SH-SY5Y cells expressing soluble intracellular phospho-tau. Because the phagocytic capacity of microglial cells is highly induced by apoptotic signals in the affected neurons, we postulate that accumulation of intraneuronal soluble phospho-tau might trigger microglial degeneration in the AD hippocampus. This microglial vulnerability in AD pathology provides new insights into the immunological mechanisms underlying the disease progression and highlights the need to improve or develop new animal models, as the current models do not mimic the microglial pathology observed in the hippocampus of AD patients.

KeywordsAlzheimer Microglia Pathology Human brain Hippocampus Elisabeth Sanchez-Mejias and Victoria Navarro contributed equally to this work. Antonia Gutierrez and Javier Vitorica are co-senior authors.

Electronic supplementary materialThe online version of this article doi:10.1007-s00401-016-1630-5 contains supplementary material, which is available to authorized users.

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Author: Elisabeth Sanchez-Mejias - Victoria Navarro - Sebastian Jimenez - Maria Sanchez-Mico - Raquel Sanchez-Varo - Cristina Nuñez


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