Reversal of neuronal tau pathology, metabolic dysfunction, and electrophysiological defects via adiponectin pathway-dependent AMPK activation.

Autor:	McGregor ER; Division of Geriatrics, Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI.; Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI., Lasky DJ; Department. of Neuroscience, Univ. of Wisconsin-Madison, Madison, WI., Rippentrop OJ; Department. of Neuroscience, Univ. of Wisconsin-Madison, Madison, WI., Clark JP; Division of Geriatrics, Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI., Wright SLG; Department. of Neuroscience, Univ. of Wisconsin-Madison, Madison, WI., Jones MV; Department. of Neuroscience, Univ. of Wisconsin-Madison, Madison, WI., Anderson RM; Division of Geriatrics, Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI.; Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI.; GRECC William S. Middleton Memorial Veterans Hospital, Madison, WI.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 07. Date of Electronic Publication: 2024 Feb 07.
DOI:	10.1101/2024.02.07.579204
Abstrakt:	Changes in brain mitochondrial metabolism are coincident with functional decline; however, direct links between the two have not been established. Here, we show that mitochondrial targeting via the adiponectin receptor activator AdipoRon (AR) clears neurofibrillary tangles (NFTs) and rescues neuronal tauopathy-associated defects. AR reduced levels of phospho-tau and lowered NFT burden by a mechanism involving the energy-sensing kinase AMPK and the growth-sensing kinase GSK3b. The transcriptional response to AR included broad metabolic and functional pathways. Induction of lysosomal pathways involved activation of LC3 and p62, and restoration of neuronal outgrowth required the stress-responsive kinase JNK. Negative consequences of NFTs on mitochondrial activity, ATP production, and lipid stores were corrected. Defects in electrophysiological measures (e.g., resting potential, resistance, spiking profiles) were also corrected. These findings reveal a network linking mitochondrial function, cellular maintenance processes, and electrical aspects of neuronal function that can be targeted via adiponectin receptor activation. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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