Characterizing a potential role for TREM2 in modulating tau pathogenesis in response to Abeta

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

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Abstract

PROJECT SUMMARY Alzheimer's disease (AD) is defined by the appearance of two defining pathologies, namely A?-amyloid plaques and neurofibrillary tangles enriched with hyperphosphorylated Tau. Accumulation of A? precedes the appearance of pathological Tau, and although correlative evidence indicates that A? proteotoxicity and Tau pathology, molecular mechanisms defining how A? can directly drive Tau pathogenesis are yet elusive. Recent correlative evidence indicates a role for dysfunction of the microglial immune receptor, Trem2 in enhancing Tau pathogenesis in regions enriched with A? plaques in AD mouse models. Interestingly, our previous results indicate that TREM2 is a potential A? receptor that directly binds and transduces proteotoxic A? signals to drive microglial activation. Given that Trem2 (and the R47H TREM2 variant in humans) is a potent risk factor for AD onset, it seems likely that TREM2 can be a potential link between A? and Tau pathology, and potentially modulates Tau pathogenesis with A? exposure. Here, we present preliminary results suggesting that Trem2 deletion (KO) in microglia can enhance Tau dispersion from the medial entorhinal cortex (MEC) to the hippocampus, which manifests in behavioral memory impairment and synaptic dysfunction. Transcriptomic analysis of Trem2 KO microglia indicates differential expression of exosomal components, and upregulation of machinery such as Atg12 which drive endosome trafficking and exosomal biogenesis. Our preliminary results in vitro also indicate that microglial Trem2 deletion can enhance transneuronal Tau transduction, which implicates a model where Trem2 deletion may enhance intraneuronal Tau dispersion during AD onset. Our previous results indicate that A? oligomers can induce Syk activation, whereas prolonged A? exposure can result in progressive renormalization of Syk activity, suggesting that chronic A? exposure can ?desensitize? microglial TREM2 signaling. Given that the TREM2 R47H likely confers loss-of-function, we will determine whether enhancement of exosome pathways, namely upregulation of Atg12, and/or suppression of the mTOR pathway mediate enhanced Tau pathogenesis with Trem2 deletion, or TREM2 R47H knock-in (KI) in microglia. We will also establish whether long-term A? treatment can affect Tau uptake, enhance sorting into exosomes, and extrusion in microglia, and compare differences in exosomal Tau trafficking in WT, Trem2 KO and R47H KI microglia. Using a Tau FRET biosensor cell line system (Tau RD), we will also assay potency of extruded exosomal Tau with long-term A? treatment in WT, Trem2 KO and R47H KI backgrounds, and determine whether alterations in Atg12 or mTOR pathways can affect Tau seeding potency. Together, completion of these Aims will provide insight into TREM2 as an intermediary A? sensor which initially suppresses Tau dispersion with acute A? exposure. Chronic A? exposure, however, desensitizes the TREM2 signaling pathway, thereby potentially aggravating Tau exosomal trafficking pathways, and enhancing Tau seeding potency. These findings may lead to novel therapies to uncouple A? and Tau pathogenesis in AD.