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A role for the autophagy receptor NBR1 in the degradation of Tau aggregates

ABSTRACT: Neurofibrillary tangles (NFTs), comprising hyperphosphorylated and aggregated Tau protein, are a primary neuropathological feature of Alzheimer's Disease (AD). In patients, the formation and spread of NFTs across the brain correlate with cognitive decline. However, the mechanisms driving Tau aggregation and leading to the subsequent neuronal dysfunction are not fully understood. In this study, we explored proteomic and phosphoproteomic changes resulting from the seed-induced aggregation of endogenous Tau in human neurons derived from induced pluripotent stem (iPS) cells. We discovered previously undescribed phosphorylation sites on NBR1, an autophagy receptor, which were significantly altered by Tau aggregation in vitro. We further show that NBR1 directly interacts with phosphorylated Tau and Tau aggregates in various cell models. This interaction is associated with autophagic Tau degradation in HEK cells, and siRNA-mediated knockdown of NBR1 significantly increases Tau aggregate levels in iPS-derived neurons. Additionally, we find that NBR1 specifically interacts with phospho-Tau in human AD brain, underscoring the relevance of our findings to the human disease. These insights provide a deeper understanding of the molecular interactions between autophagy receptors and Tau pathology in AD and reveal a role for NBR1 as an important receptor for pathological forms of Tau.

INSTRUMENT(S): Orbitrap Exploris 240

ORGANISM(S): Human

SUBMITTER: Marie Neu

PROVIDER: MSV000096965 | MassIVE | Mon Jan 27 00:38:00 GMT 2025

SECONDARY ACCESSION(S): PXD060223

REPOSITORIES: MassIVE

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Project description:Background:Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease(AD), which is closely related to tau pathology and hippocampal impairment. Given the heterogeneity of brain neurons, the precise role of different brain neurons in terms of their sensitivity to tau accumulation and contribution to AD-like social memory loss remains unclear and requires further investigation. Methods: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic experiments, social behavioral test, hippocampal electrophysiology, immunofluorescent staining and in vivo optical fiber recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine their effects on social memory in mice. Results: By proteomic and phosphoproteomic analyses, we identified the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, not dorsal CA1 (dCA1), but vCA1, especially its excitatory and PV neurons, were fully filled with mislocated and phosphorylated tau. Overexpression of human Tau (hTau) in excitatory and PV neurons respectively mimicked AD-like tau accumulation, significantly inhibited the neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythm and time-window efficiently ameliorated tau-impaired social memory. Significantly, one-month administration of UA efficiently decreased tau accumulation via autophagy in a TFEB (transcription factor EB)-dependent manner and recovered vCA1 microcircuit to ameliorate tau-impaired social memory.Conclusion: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1, and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for AD treatment in the future.

Project description:Neurons are postmitotic cells that are highly sensitive to proteotoxic insults and reliant on tight protein quality control. Several forms of autophagy co-exist in neurons to maintain proteostasis. Defective autophagic pathways are one of the key hallmarks of the aging and neurodegenerative brains. Chaperone-mediated autophagy (CMA) declines in neurons in aging and neurodegenerative diseases including Alzheimer’s (AD) and Parkinson’s disease. CMA loss in neurons leads to protein aggregation, neuronal hyperactivity, neurodegeneration, and cognitive decline, all reminiscent of brain again. Conversely, pharmacological enhancement of CMA reduces pathological tau and β-amyloid accumulation, mitigates neuronal hyperactivity and seizure susceptibility and ameliorates cognitive decline in multiple tauopathy mouse models. The molecular mechanism underlying the beneficial role of CMA activation in AD is largely unknow. Furthermore, neuronal hyperactivity has recently been proposed as an early hallmark of AD. However, the mechanisms underlying early neuronal hyperactivity in AD are also not fully understood. To investigate these molecular mechanisms, we performed quantitative proteomics in an AD mouse model in early disease following CMA activation. The study analyzed total as well as aggregating proteome in hippocampus of triple-transgenic (x3TG) AD mice (expressing APPSwe, PS2N141I, and hTauP301L) following CMA activation with CA77.1 from 4-6 months of age. 5-6 samples per group were analyzed. Following bottom-up analysis, the enrichment analysis – GO, Ingenuity pathway analysis (IPA) and String analysis identified several pathways predicting aberrant synaptogenesis and increased activation of excitatory synaptic proteome including glutamate receptor signaling which was corrected by CMA activation. CMA activation also reverted the enrichment of synaptic proteins in the aggregates in early AD hippocampus which may restore their aggregation-driven loss of function.

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A role for the autophagy receptor NBR1 in the degradation of Tau aggregates

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