| First Author | Baltissen D | Year | 2023 |
| Journal | Front Cell Neurosci | Volume | 17 |
| Pages | 1106176 | PubMed ID | 36779015 |
| Mgi Jnum | J:343351 | Mgi Id | MGI:7436125 |
| Doi | 10.3389/fncel.2023.1106176 | Citation | Baltissen D, et al. (2023) APPsalpha rescues CDK5 and GSK3beta dysregulation and restores normal spine density in Tau transgenic mice. Front Cell Neurosci 17:1106176 |
| abstractText | 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 Abeta plaques, derived from the beta-amyloid precursor protein APP. Whereas Abeta is produced by amyloidogenic APP processing, APP processing along the competing non-amyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsalpha. Recently, we demonstrated that APPsalpha has therapeutic effects in transgenic AD model mice and rescues Abeta-dependent impairments. Here, we examined the potential of APPsalpha to regulate two major Tau kinases, GSK3beta 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 GSK3beta and CDK5 activity in the hippocampus of THY-Tau22 mice. Interestingly, AAV-mediated intracranial expression of APPsalpha in THY-Tau22 mice efficiently restored normal GSK3beta 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-APPsalpha 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-APPsalpha injection. Moreover, AAV-APPsalpha reduced misfolded (MC1) Tau species, particularly in somatodendritic compartments of CA1 pyramidal neurons. Finally, we show that AAV-APPsalpha upregulated PSD95 expression and rescued deficits in spine density of THY-Tau22 mice. Together our findings suggest that APPsalpha holds therapeutic potential to mitigate Tau-induced pathology. |
