Tau target identification reveals NSF‐dependent effects on AMPA receptor trafficking and memory formation. (22nd August 2022)

• Record Type: Journal Article
• Authors: Prikas, Emmanuel; Paric, Esmeralda; Asih, Prita R; Stefanoska, Kristie; Stefen, Holly; Fath, Thomas; Poljak, Anne; Ittner, Arne
• Is Part Of: EMBO journal. Volume 41:Number 18(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-08-22
• Subjects: AMPA receptor -- associative learning -- interactome -- proximity labelling -- tau; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2021110242
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Microtubule‐associated protein tau is a central factor in Alzheimer's disease and other tauopathies. However, the physiological functions of tau are unclear. Here, we used proximity‐labelling proteomics to chart tau interactomes in primary neurons and mouse brains in vivo . Tau interactors map onto pathways of cytoskeletal, synaptic vesicle and postsynaptic receptor regulation and show significant enrichment for Parkinson's, Alzheimer's and prion disease. We find that tau interacts with and dose‐dependently reduces the activity of N‐ethylmaleimide sensitive fusion protein (NSF), a vesicular ATPase essential for AMPA‐type glutamate receptor (AMPAR) trafficking. Tau‐deficient (tau −/− ) neurons showed mislocalised expression of NSF and enhanced synaptic AMPAR surface levels, reversible through the expression of human tau or inhibition of NSF. Consequently, enhanced AMPAR‐mediated associative and object recognition memory in tau −/− mice is suppressed by both hippocampal tau and infusion with an NSF‐inhibiting peptide. Pathologic mutant tau from mouse models or Alzheimer's disease significantly enhances NSF inhibition. Our results map neuronal tau interactomes and delineate a functional link of tau with NSF in plasticity‐associated AMPAR‐trafficking and memory. Synopsis: Tau is associated with cognitive decline in Alzheimer's disease. How tau contributes to physiological functions of learning and memory remains largely unknown. This study maps tau interactomes in mouse brain and neurons using proximity labelling. Direct interaction of tau with the vesicle and receptor trafficking factor NSF inhibits NSF ATPase activity and controls synaptic glutamate receptors underlying associative learning. BioID proximity labelling maps tau interactions in mouse brain. The tau interactome is enriched for neurodegenerative disease‐linked factors, and for vesicular and synaptic receptor regulators. Tau and the NSF ATPase regulate AMPA Receptor trafficking, a central component of synaptic plasticity and learning. Tau‐dependent inhibition of NSF correlates with learning in object recognition and fear conditioning. Abstract : Proximity‐labelling in mouse brain and neurons identify targets of the Alzheimer's disease‐associated protein tau in glutamate receptor trafficking and memory formation.