Microglia become hypofunctional and release metalloproteases and tau seeds after phagocytosing live neurons with P301S tau aggregates

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 transgenic mice due to neuronal tau aggregate-induced exposure of the 'eat me' signal phosphatidylserine. Here we show that after phagocytosis, microglia become hypophagocytic while releasing seed-competent insoluble tau aggregates. These microglia activate acidic β-galactosidase, and release senescence-associated cytokines and matrix remodeling enzymes alongside tau, indicating a senescent phenotype. In particular, the marked NFκB-induced activation of matrix metalloprotease 3 (MMP3/stromelysin1) was replicated in the brains of P301S mutant tau transgenic mice, and in human brains from tauopathy patients. These data show that microglia that have been activated to ingest live neurons with tau aggregates behave hormetically, becoming hypofunctional while acting as vectors of tau aggregate spreading.

Impairment of the glial phagolysosomal system drives prion-like propagation in aDrosophilamodel of Huntington’s disease

“…We postulate that persistence of aggregates in faulty endolysosomes promotes formation and/or release of degradation-resistant aggregates with enhanced toxicity and seeding capacity. This hypothesis is in agreement with recent studies in tauopathy models showing that Ab aggregation occurs secondary to lysosome deacidification and membrane permeabilization (Lee et al, 2022), and hypophagocytic glia contribute to tau aggregate propagation (Hopp et al, 2018;Brelstaff et al, 2021). Release of seeding-competent aggregates from dysfunctional lysosomes could occur via active exocytosis, perhaps in an effort to alleviate cell toxicity, or passively due to vesicle rupture (Flavin et al, 2017;Falcon et al, 2018;Yuste-Checa et al, 2021).…”

The innate immune response in tauopathies

“…The authors of this study went on to show that microglial phagocytosis of pathogenic tau, either from PS19 mice or P301L adeno-associated virus injections, lead to the release of exosomes filled with tau seeds capable of inciting prionlike spread of tauopathy [90]. Interestingly, isolated human and mouse microglia have been shown to house tau seeds and secrete them when cultured in vitro, illustrating the incomplete digestion of tau that can occur in microglia [122,123]. Likewise, the production of pro-inflammatory cytokines by activated microglia, such as those downstream of NF-κB signaling [124], has also been shown to promote subsequent stress kinase cascade activation and tau phosphorylation within neurons [125][126][127] (Fig.…”