Novel Neuroprotective Roles for the Alzheimer's Disease Risk Gene SORLA in Tau Pathology and Pathogenesis - Numerous mutational variants in the SORLA (SORL1) gene are associated with increased Alzheimer’s disease (AD) risk, and although growing evidence from our group and others support a neuroprotective role for SORLA in suppressing effects associated with Aβ, virtually nothing is known with respect to whether SORLA can modulate proteotoxic effects associated with tau. Here, we present evidence that transgenic upregulation of SORLA (“SORLA TG”) can reduce tau phosphorylation, as well as pathological ventricular dilation in 9 month- old (9MO) PS19 (P301S tau) mouse brain. Proteomic analysis reveals changes in proteomic profiles related to synaptic dysfunction and microglial activation, including upregulation of APOE and the complement component, C1q in PS19 mouse hippocampus; these changes were largely suppressed in SORLA TG/PS19 hippocampus, indicating that SORLA upregulation can potentially reverse pathological changes associated with tau proteotoxicity. Histological analysis indicates that C1q and astrogliosis is highly upregulated in PS19 hippocampus, and these effects were reduced in SORLA TG/PS19 animals. Interestingly, C1q has been previously shown to label synapses for microglial uptake and elimination in both J20 (hAPP) and PS19 mouse brain, which together, suggests that SORLA potentially mediates neuroprotective effects through suppression of deleterious changes associated with synaptic factors and gliosis in PS19 hippocampus. Our prior work also demonstrates that upregulation of a cleaved soluble SORLA (sSORLA) form in SORLA TG animals is also protective in neurons, and enhances neurite regeneration with neuronal injury. We therefore hypothesize that SORLA can mediate neuroprotective effects to limit tau pathology/proteotoxicity and determine here, whether and how SORLA overexpression, deletion or sSORLA can affect tau pathology and pathogenesis. As our results demonstrate that SORLA TG/PS19 animals can reverse pathological and proteomic features associated with late-stage (9MO) tau pathology, we will also characterize changes at early and mid- stages of tau pathology, and characterize cell-type specific transcriptomic changes in 9MO hippocampus in PS19 mice that may be potentially suppressed in SORLA TG/PS19 animals by snRNAseq analysis. We will also characterize effects of SORLA upregulation on glial-associated synaptic uptake and pruning in PS19 and SORLA TG/PS19 animals, and compare effects of intraneuronal tau dispersion from the MEC to DG region in wildtype (WT) vs SORLA TG brain using an AAV-tau propagation model used in our lab (Aim 1) (Zhu et al., 2022). We will also determine effects of SORLA deletion on tau pathology, gliosis and synpatotoxicity (Aim 2), and characterize effects of AD-associated SORLA mutational variants (T2134M, E2055X) that potentially upregulate sSORLA on microglial function and SORLA/sSORLA expression in an ESC-based human microglia cells in vitro, and in human microglial xenotransplant models in PS19/hMCSF mouse brain in vivo (Aim 3). Together, results from this study will provide insight into a previously undescribed role for SORLA and sSORLA in tau pathology.
