Abstract
The microtubule-associated protein tau aggregates in multiple neurodegenerative diseases, causing inflammation and changing the inflammatory signature of microglia by unknown mechanisms. We have shown that microglia phagocytose live neurons containing tau aggregates cultured from P301S tau mice due to neuronal tau aggregate-induced exposure of the “eat me” signal phosphatidylserine. Here, we show that after phagocytosing tau aggregate-bearing neurons, microglia become hypophagocytic while releasing seed-competent insoluble tau aggregates. These microglia express a senescence-like phenotype, demonstrated by acidic β-galactosidase activity, secretion of paracrine senescence-associated cytokines, and maturation of matrix remodeling enzymes, results that are corroborated in P301S mouse brains and ex vivo brain slices. In particular, the nuclear factor κB–dependent activation of matrix metalloprotease 3 (MMP3/stromelysin1) was replicated in brains from patients with tauopathy. These data show that microglia that have been activated to ingest live tau aggregates-bearing neurons behave hormetically, becoming hypofunctional while acting as vectors of tau aggregate spreading.
Highlights
Aggregation of the protein tau from a soluble unfolded state to an insoluble, sheet–enriched filamentous structure underlies numerous human neurodegenerative diseases known as tauopathies [1]
conditioned medium (CM) were assayed for human tau by enzyme-linked immunosorbent assay (ELISA) after 4 days from either monocultured neurons or microglia, from microglia cocultured with neurons, or from microglia reisolated after coculture and cultured alone for a further 4 days (Fig. 1B)
Tau (4.54 ± 0.49 pg/ml) was detected in the CM from 5M P301S dorsal root ganglion neurons (DRGn)-microglia cocultures and continued to be present even when microglia were reisolated from the cocultures and cultured alone for a further 4 days (8.4 ± 1.3 pg/ml, P = 0.185 compared to 5M P301S DRGn-microglia cocultures unpaired t test), suggesting that the source of tau was microglia that had phagocytosed neurons with tau aggregates (Fig. 1B)
Summary
Aggregation of the protein tau from a soluble unfolded state to an insoluble, sheet–enriched filamentous structure underlies numerous human neurodegenerative diseases known as tauopathies [1]. We have previously shown that inflammation is present in human mutant P301S tau mice (P301S tau) [11] and that live cultured dorsal root ganglion neurons (DRGn) from P301S tau mice display PtdSer on the external leaflet of their plasma membranes, which recruits cocultured microglia that phagocytose them while still viable [9]. This process is accompanied by secretion of the opsonin milk fat globule epidermal growth factor 8 (MFGE8) and nitric oxide production and leads to the transfer of tau aggregates inside the phagocytosed neurons to the microglia [9]. These data implicate microglia in the pathological loss of neurons and synapses in tauopathy by intensifying phagocytic activity to damaging levels
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