Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration

Abstract

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

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

“…The utilization of post mortem human samples was approved by the corresponding biobank ethics committees and the “Comite de Etica de la Investigacion (CEI), Hospital Virgen del Rocio”, Seville, Spain. All the subjects (Braak 0, II, III–IV and V–VI) in this study are identical to those reported by us previously (Sanchez‐Mejias et al, 2016). All cases were scored for Braak tau pathology.…”

“…Therefore, altogether our data support the idea of dysfunctional astroglial cells in the context of AD. In this sense, we have recently reported that microglial cells in the hippocampus of AD brains display a degenerative phenotype (Sanchez‐Mejias et al, 2016). Therefore, the functional impairment of glial cells in AD as a potential driver of disease progression deserves particular consideration.…”

“…Retrotanscription and qPCR were performed as described previously (Sanchez‐Mejias et al, 2016). Briefly, retrotranscription (4 g of total RNA as template) was performed with the High Capacity cDNA Archive Kit (Applied Biosystems, Foster City, CA).…”

“…Western blots were performed as previously described (Sanchez‐Mejias et al, 2016). Proteins (15 μg) were loaded on 4–20% sodium dodecyl sulfate‐Tris‐Glycine‐polyacrylamide gel electrophoresis (Bio‐Rad, Hercules, CA), transferred to nitrocellulose (Optitran, GE Healthcare Life Sciences, Marlborough, MA) and incubated with anti‐GFAP antibody.…”

Patterns of Microglial Cell Activation in Alzheimer Disease and Frontotemporal Lobar Degeneration

“…For instances, a recent study reported that microglial cells in the hippocampi of severely affected Braak stage V-VI samples were no longer even associated with neuritic plaques or with the vascular amyloid, highlighting the range of microglial alterations [40]. …”