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Reversal of neuronal tau pathology, metabolic dysfunction, and electrophysiological defects via adiponectin pathway-dependent AMPK activation.
McGregor, Eric R; Lasky, Danny J; Rippentrop, Olivia J; Clark, Josef P; Wright, Samantha L G; Jones, Mathew V; Anderson, Rozalyn M.
Afiliación
  • McGregor ER; Division of Geriatrics, Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI.
  • Lasky DJ; Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI.
  • Rippentrop OJ; Department. of Neuroscience, Univ. of Wisconsin-Madison, Madison, WI.
  • Clark JP; Department. of Neuroscience, Univ. of Wisconsin-Madison, Madison, WI.
  • Wright SLG; Division of Geriatrics, Department of Medicine, SMPH, University of Wisconsin-Madison, Madison, WI.
  • Jones MV; Department. of Neuroscience, Univ. of Wisconsin-Madison, Madison, WI.
  • Anderson RM; Department. of Neuroscience, Univ. of Wisconsin-Madison, Madison, WI.
bioRxiv ; 2024 Feb 07.
Article en En | MEDLINE | ID: mdl-38370802
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos