TFEB-vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy

Abstract

Transcription factor EB (TFEB) mediates gene expression through binding to the Coordinated Lysosome Expression And Regulation (CLEAR) sequence. TFEB targets include subunits of the vacuolar ATPase (v-ATPase) essential for lysosome acidification. Single nucleus RNA-sequencing (snRNA-seq) of wild-type and PS19 (Tau) transgenic mice identified three unique microglia subclusters in Tau mice that were associated with heightened lysosome and immune pathway genes. To explore the lysosome-immune relationship, we specifically disrupted the TFEB-v-ATPase signaling by creating a knock-in mouse line in which the CLEAR sequence of one of the v-ATPase subunits, Atp6v1h, was mutated. We show that the CLEAR mutant exhibited a muted response to TFEB, resulting in impaired lysosomal acidification and activity. Crossing the CLEAR mutant with Tau mice led to higher tau pathology but diminished microglia response. These microglia were enriched in a subcluster low in mTOR and HIF-1 pathways and was locked in a homeostatic state. Our studies demonstrate a physiological function of TFEB-v-ATPase signaling in maintaining lysosomal homoeostasis and a critical role of the lysosome in mounting a microglia and immune response in tauopathy and Alzheimer disease.

Cell autonomous microglia defects in a stem cell model of frontotemporal dementia

“…TREM2-dependent mTOR signaling is crucial to sustain biosynthetic and energy metabolism in microglia 78 and consistent with this, we observed a dysregulation of genes involved in glycolysis and a selective upregulation of genes involved in mitochondrial oxidative phosphorylation in MAPT IVS10+16 iMGLs. Maintenance of lysosomal homeostasis is crucial to controlling microglial mTOR levels and initiating immune responses to tau pathology in the tau-P301S tauopathy mouse model 108 . Microglia activation also induces mitochondrial alterations and initiates a metabolic shift from oxidative phosphorylation to glycolysis 109 .…”

Whole organism snRNA-seq reveals systemic peripheral changes in Alzheimer’s Disease fly models

“…Studying cell vulnerability in AD is important to understand disease progression, reveal biomarkers, and identify therapeutic targets. snRNA-seq serves as an ideal method to study cell vulnerability and several recent studies have employed snRNA-seq in different AD models and human patients (Lau et al, 2020;Mathys et al, 2023;Sziraki et al, 2023;Wang et al, 2024;Wu et al, 2023). Out of necessity, most of these studies have focused on a specific brain region and identified specific cell types that are selectively vulnerable.…”

“…For example, in the human prefrontal cortex, it was found that the most vulnerable cell types in AD tissues are three subtypes of SST+ inhibitory neurons (Mathys et al, 2023). In a PS19 AD mouse model, we found that granule cells in the hippocampus show the highest vulnerability among different types of neurons (Wang et al, 2024). Here, we took a novel approach and focused on comprehensively comparing peripheral sensory neurons with CNS neurons in AD models.…”

Complement C3aR signaling: Immune and metabolic modulation and its impact on Alzheimer's disease

“…In the context of AD, recent studies indicate that metabolic defects in microglia contribute to AD [76][77][78][79][80][81][82][83][84]. Microglia's survival and function depend on adequate energy supply.…”