Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that manifests sequential Aβ and tau brain pathology with age-dependent onset. Variants in the microglial immune receptor TREM2 are associated with enhanced risk of onset in sporadic Alzheimer’s disease (AD). While recent studies suggest TREM2 dysfunction can aggravate tau pathology, mechanisms underlying TREM2-dependent modulation of tau pathology remains elusive. Methods: Here, we characterized differences in progressive tau spreading from the medial entorhinal cortex (MEC) to the hippocampus in wildtype (WT) and Trem2 knockout (KO) mice by injection of AAV-P301L tau into the MEC, and correlated changes in hippocampal tau histopathology with spatial and fear memory. We also compared effects of intraneuronal dispersion between cultured microglia and neurons using a microfluidic dispersion assay, analyzed differences in microglial tau trafficking following uptake, and quantified exosomal tau secretion and pathogenicity from purified WT and Trem2 KO exosomes. Results: Trem2 deletion in mice (Trem2 KO) can enhance tau spreading from the medial entorhinal cortex (MEC) to the hippocampus, which coincides with impaired synaptic function and memory behavior. Trem2 deletion in microglia enhances intraneuronal dispersion of tau in vitro between neuronal layers cultured in a microfluidic chamber, and the presence of exosome inhibitors can significantly reduce tau in exosomes and extracellular media from tau-loaded microglia. Although microglial Trem2 deletion has no effect on tau uptake, Trem2 deletion enhances distribution to endosomal and cellular pre-exosomal compartments following internalization. Trem2 deletion has little effect on exosome size, however, proteomic analysis indicates that Trem2 deletion can modulate changes in the microglial proteomic landscape with tau and LPS/ATP treatment conditions associated with exosome induction. Furthermore, exosomes from Trem2 KO microglia show elevated tau levels, and feature enhanced tau-seeding capacity in a tau FRET reporter line compared to exosomes from WT microglia. Conclusion: Together, our results reveal a role for Trem2 in suppressing exosomal tau pathogenicity, and demonstrates that Trem2 deletion can enhance tau trafficking, distribution and seeding through microglial exosomes. Graphical

Ischemic stroke promotes monocyte recruitment to the injured brain and their differentiation into monocyte-derived macrophages (MDMs). These cells contribute to debris clearance but may also exacerbate neuroinflammation. However, the heterogeneity of MDM subsets and the phenotypic transitions that shape MDM functional states during the subacute phase of stroke remain incompletely characterized. To address this, we first performed single-cell RNA sequencing (scRNA-seq) to define the transcriptional landscape of the mouse brain 48 h after transient middle cerebral artery occlusion/reperfusion compared with sham controls. Reclustering of macrophage-lineage cells identified multiple MDM subsets, including a distinct Cd68^hi/Ctsd^hi MDM subset enriched for lysosomal and lipid-processing gene expression programs. Cell trajectory inference supported a transition from early recruited MDMs toward the Cd68^hi/Ctsd^hi state, accompanied by induction of transcriptomic networks that drive MDM function to favor a clearance-competent phenotype in response to ischemic stroke. Complementary single-cell ATAC sequencing (scATAC-seq) demonstrated cell type-specific chromatin remodeling after stroke and revealed MDM subclusters with accessibility at key loci regulating lysosomal function and lipid metabolism. Together, our findings define a cellular and regulatory framework of the subacute post-stroke brain and identify a lysosome-enriched Cd68^hi/Ctsd^hi MDM trajectory, highlighting endolysosomal and lipid-processing programs during early stroke recovery.

A role for the trafficking receptor SORLA (Sortilin-related receptor containing LDLR class A repeats) in reducing Aβ levels has been well established; however, relatively little is known with respect to whether and how SORLA can potentially affect tau pathology in vivo. Here, we show that transgenic SORLA up-regulation (SORLA TG) can attenuate pathological effects in aged PS19 (P301S tau) mouse brain, including tau phosphorylation and seeding, ventricle dilation, synapse loss, long-term potentiation (LTP) impairment, and glial hyperactivation. Proteomic analysis indicates attenuation of PS19 profiles in PS19/SORLA TG hippocampus, including pathological changes in synapse-related proteins and key drivers of synaptic dysfunction such as ApoE and C1q. Single-nucleus RNA sequencing analysis reveals suppression of PS19 signatures with SORLA up-regulation and identifies a previously unrecognized involvement of Sema4D-PlexinB1/B2 signaling in glial pathology. In contrast, SORLA deletion exacerbates tau seeding and aggregation, glial hyperactivation, and PlxnB1/B2 induction in PS19 hippocampus. These results indicate that SORLA confers neuroprotection against tau toxicity in the PS19 mouse brain.