APPsα rescues CDK5 and GSK3β dysregulation and restores normal spine density in Tau transgenic mice

• Verfasst von: Baltissen, Danny [VerfasserIn]
• Verfasst von: Bold, Charlotte S. [VerfasserIn]
• Verfasst von: Rehra, Lena [VerfasserIn]
• Verfasst von: Banićević, Marija [VerfasserIn]
• Verfasst von: Fricke, Justus [VerfasserIn]
• Verfasst von: Just, Jennifer [VerfasserIn]
• Verfasst von: Ludewig, Susann [VerfasserIn]
• Verfasst von: Buchholz, Christian J. [VerfasserIn]
• Verfasst von: Korte, Martin [VerfasserIn]
• Verfasst von: Müller, Ulrike C. [VerfasserIn]
• Titel: APPsα rescues CDK5 and GSK3β dysregulation and restores normal spine density in Tau transgenic mice
• Verf.angabe: Danny Baltissen, Charlotte S. Bold, Lena Rehra, Marija Banićević, Justus Fricke, Jennifer Just, Susann Ludewig, Christian J. Buchholz, Martin Korte and Ulrike C. Müller
• E-Jahr: 2023
• Jahr: 26 January 2023
• Umfang: 21 S.
• Fussnoten: Gesehen am 14.04.2023
• Titel Quelle: Enthalten in: Frontiers in cellular neuroscience
• Ort Quelle: Lausanne : Frontiers Research Foundation, 2007
• Jahr Quelle: 2023
• Band/Heft Quelle: 17(2023), Artikel-ID 1106176, Seite 1-21
• ISSN Quelle: 1662-5102
• DOI: doi:10.3389/fncel.2023.1106176
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1842669680
• K10plus-PPN:
  Universitätsbibliothek
• Lokale URL UB: Zum Volltext

Abstract

The Tau protein can be phosphorylated by numerous kinases. In Alzheimer’s disease (AD) hyperphosphorylated Tau species accumulate as neurofibrillary tangles that constitute a major hallmark of AD. AD is further characterized by extracellular Aβ plaques, derived from the β-amyloid precursor protein APP. Whereas Aβ is produced by amyloidogenic APP processing, APP processing along the competing non-amyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aβ-dependent impairments. Here, we examined the potential of APPsα to regulate two major Tau kinases, GSK3β and CDK5 in THY-Tau22 mice, a widely used mouse model of tauopathy. Immunohistochemistry revealed a dramatic increase in pathologically phosphorylated (AT8 and AT180) or misfolded Tau species (MC1) in the hippocampus of THY-Tau22 mice between 3 and 12 months of age. Using a highly sensitive radioactive kinase assay with recombinant human Tau as a substrate and immunoblotting, we demonstrate an increase in GSK3β and CDK5 activity in the hippocampus of THY-Tau22 mice. Interestingly, AAV-mediated intracranial expression of APPsα in THY-Tau22 mice efficiently restored normal GSK3β and CDK5 activity. Western blot analysis revealed upregulation of the CDK5 regulatory proteins p35 and p25, indicating CDK5 hyperactivation in THY-Tau22 mice. Strikingly, AAV-APPsα rescued p25 upregulation to wild-type levels even at stages of advanced Tau pathology. Sarkosyl fractionation used to study the abundance of soluble and insoluble phospho-Tau species revealed increased soluble AT8-Tau and decreased insoluble AT100-Tau species upon AAV-APPsα injection. Moreover, AAV-APPsα reduced misfolded (MC1) Tau species, particularly in somatodendritic compartments of CA1 pyramidal neurons. Finally, we show that AAV-APPsα upregulated PSD95 expression and rescued deficits in spine density of THY-Tau22 mice. Together our findings suggest that APPsα holds therapeutic potential to mitigate Tau-induced pathology.