Dataset Information

Axonal tau reduction ameliorates tau and amyloid pathology in a mouse model of Alzheimer’s disease

ABSTRACT: Pathological deposition of hyperphosphorylated tau in the brain closely correlates with the course of Alzheimer´s disease (AD). Tau pathology occurs first in axons of affected neurons and tau removal from axons might thus be an early intervention strategy. We report that the RNA-binding protein hnRNP R facilitates the axonal localization of the Mapt mRNA encoding tau. Mapt mRNA and tau protein were reduced in axons but not cell bodies of primary neurons cultured from hnRNP R knockout mice. Brains of 5xFAD mice deficient for hnRNP R contained less phospho-tau aggregates and amyloid-β plaques in cortex and hippocampus. Treatment of neurons with antisense oligonucleotides (MAPT-ASOs) to block hnRNP R binding to Mapt similarly reduced axonal tau levels, and intracerebroventricular injection of a MAPT-ASO ameliorated the phospho-tau and plaque load in 5xFAD mice. Lowering of tau selectively in axons thus represents an innovative therapeutic perspective for treatment of AD and other tauopathies.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Mario Oroshi

LAB HEAD: Matthias Mann

PROVIDER: PXD053387 | Pride | 2025-08-04

REPOSITORIES: Pride

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			Action	DRS
	20240530_OA4_ViAl_SA_FAIMS40_A803_VA10c-20240529_JaBa_Neat_11_P01-G1_9676.raw	Raw
	20240530_OA4_ViAl_SA_FAIMS40_A803_VA10c-20240529_JaBa_Neat_12_P01-G2_9677.raw	Raw
	20240530_OA4_ViAl_SA_FAIMS40_A803_VA10c-20240529_JaBa_Neat_13_P01-G3_9678.raw	Raw
	20240530_OA4_ViAl_SA_FAIMS40_A803_VA10c-20240529_JaBa_Neat_14_P01-G4_9679.raw	Raw
	20240530_OA4_ViAl_SA_FAIMS40_A803_VA10c-20240529_JaBa_Neat_15_P01-G5_9680.raw	Raw

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Axonal tau reduction ameliorates tau and amyloid pathology in a mouse model of Alzheimer's disease.

Zare Abdolhossein A Salehi Saeede S Bader Jakob M JM Wiessler Anna-Lena AL Prokesch Manuela M Albrecht Vincent V Villmann Carmen C Mann Matthias M Briese Michael M Sendtner Michael M

Translational neurodegeneration 20250729 1

<h4>Background</h4>Pathological deposition of hyperphosphorylated tau in the brain closely correlates with the course of Alzheimer's disease (AD). Tau pathology occurs in axons of affected neurons and tau removal from axons might thus be an early intervention strategy.<h4>Methods</h4>We investigated the role of the RNA-binding protein hnRNP R in axonal localization and local translation of Mapt mRNA in neurons cultured from hnRNP R knockout mice. hnRNP R knockout mice were crossed with 5×FAD mic ...[more]

PMID: 40734174

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Project description:The abnormal higher-order assembly of tau protein in neurons and glia underlies a large group of neurodegenerative diseases, including Alzheimer's disease (AD). Tau assemblies are first detected in localised brain regions and subsequently accumulate in connected networks. Prion-like propagation is thought to underlie the temporospatial accumulation of assembled tau, encompassing intracellular trafficking and trans-synaptic transfer of assembled tau species that seed the assembly of normally folded tau. Evidence suggests that extracellular vesicles (EVs), a diverse group of lipid vesicles that facilitate the intercellular transfer of bioactive molecules, mediate transfer of assembled tau seeds. However, the molecular species of assembled tau seeds in human brain are unknown. Furthermore, the identities of the EVs that mediate intercellular transfer of assembled tau and how this is achieved have not been determined. Here, we isolated sub-populations of EVs from human brain enriched in plasma membrane; endo-lysosomal; or mitochondrial proteins. We used electron cryo-tomography (cryo-ET) and single-particle electron cryo-microscopy (cryo-EM) to directly analyse the structure and molecular organisation of assembled tau seeds associated with intact EVs isolated from the brains of individuals who had AD. We found that short tau paired helical filaments (PHFs) were packaged within the lumen of large EVs enriched in endo-lysosomal proteins. The PHFs incorporated anionic molecules not observed in cell-derived PHFs, leading to a more compact filament fold. Multiple PHFs associated with one another and were linked to the luminal membrane at their ends. The PHF-containing EVs initiated propagation in directly-converted neurons, as well as in transgenic mice and a biosensor cell line. This work suggests that short PHFs are responsible for EV-mediated propagation of assembled tau in human brain. These results have broad implications for diagnostic and therapeutic strategies targeting extracellular assembled tau seeds in AD and other neurodegenerative diseases.