Sandusky-Beltran, L. A. | Search bioRxiv

bioRxiv2024

Clearing truncated tau protein restores neuronal function and prevents microglia activation in tauopathy mice

Tau protein truncated at aspartate 421 (Asp421) is a characteristic feature of Alzheimers disease (AD) and other tauopathies. It is likely to have a role in their pathogenesis by promoting tau aggregation. Here, using two tauopathy mouse models, we show that a monoclonal antibody against Asp421, 5G2, led to a) a 59-74% clearance of insoluble tau protein in the brains of JNPL3 tauopathy mice following a thirteen-week treatment period, b) a 46% decrease of tau levels in brain interstitial fluid immediately following a single dose of 5G2 as examined by brain microdialysis in awake JNPL3 mice, c) improved neuronal function and d) reduced microglial activation as determined by two-photon imaging in awake PS19 tauopathy mice, where we also found tau accumulation earlier than signs of microglial activation. For mechanistic insight using culture models, 5G2 prevented toxicity of AD brain-derived pathological tau protein, cleared intracellular tau, and prevented microgliosis. We also knocked down the intracellular Fc receptor and ubiquitin E3 ligase, TRIM21, and found a reduction in cellular retention of tau antibodies, which appeared to reduce the acute efficacy (24 h) of tau antibodies but not their longer-term efficacy (5 days). Overall, these findings strongly support the feasibility of targeting Asp421 truncated tau protein to treat tauopathies, indicate that tau-associated abnormalities of neuronal activity precede microglial activation and that antibody-mediated tau clearance via the TRIM21 pathway is mostly transient.

neuroscience↗

bioRxiv2024

Nutrient Sensing Receptor GPRC6A Regulates mTORC1 Signaling and Tau Biology

Tauopathies, including Alzheimers disease (AD), comprise microtubule-associated protein tau aggregates that cause neuronal cell death and clinical cognitive decline. Reducing overall tau abundance remains a central strategy for therapeutics; however, no disease-modifying treatment exists to date. One principal pathway for balancing cellular proteostasis includes the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Recently, arginine emerged as one of the primary amino acids to activate mTORC1 through several intracellular arginine sensors and an extracellular arginine receptor, namely the G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A). Human AD brains were previously reported with elevated mTORC1 signaling; however, it is unclear whether arginine sensing and signaling to mTORC1 plays a role in tauopathies. Herein, we examined arginine sensing associated with mTORC1 signaling in the human AD and animal models of tauopathy. We found that human AD brains maintained elevated levels of arginine sensors with potential uncoupling of arginine sensing pathways. Furthermore, we observed increased GPRC6A and arginine in the brain, accompanied by increased mTORC1 signaling and decreased autophagy in a mouse model of tauopathy (Tau PS19). We also discovered that both supplementing arginine and overexpressing GPRC6A in cell culture models could independently activate mTORC1 and promote tau accumulation. In addition, we found that suppressing GPRC6A signaling by either genetic reduction or pharmacological antagonism reduced tau accumulation, phosphorylation, and oligomerization. Overall, these findings uncover the crucial role of arginine sensing pathways in deregulating mTORC1 signaling in tauopathies and identify GPRC6A as a promising target for future therapeutics in tauopathies and other proteinopathies. Significance StatementTauopathies, including Alzheimers disease (AD), accumulate pathogenic tau protein inclusions that potentially contribute to the hyperactive mechanistic target of rapamycin complex 1 (mTORC1) signaling and eventually cause neuronal cell death. Here, we presented novel findings that AD and animal models of tauopathy maintained increased expression of arginine sensors and uncoupling of arginine sensing associated with mTORC1 signaling. We investigated the role of a putative extracellular arginine and basic L-amino acid sensing G protein-coupled receptor (GPCR) family C, group 6, member A (GPRC6A) in activating mTORC1 and accelerating pathogenic tau phenotypes in several cell models. Additionally, we showed that genetic repression or antagonism of GPRC6A signaling provides a novel therapeutic target for tauopathies and other proteinopathies.

neuroscience↗