| First Author | Manczak M | Year | 2012 |
| Journal | Hum Mol Genet | Volume | 21 |
| Issue | 11 | Pages | 2538-47 |
| PubMed ID | 22367970 | Mgi Jnum | J:183771 |
| Mgi Id | MGI:5319251 | Doi | 10.1093/hmg/dds072 |
| Citation | Manczak M, et al. (2012) Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage. Hum Mol Genet 21(11):2538-47 |
| abstractText | We recently reported increased mitochondrial fission and decreased fusion, increased amyloid beta (Abeta) interaction with the mitochondrial fission protein Drp1, increased mitochondrial fragmentation, impaired axonal transport of mitochondria and synaptic degeneration in neurons affected by AD. In the present study, we extended our previous investigations to determine whether phosphorylated tau interacts with Drp1 and to elucidate mitochondrial damage in the progression of AD. We also investigated GTPase activity, which is critical for mitochondrial fragmentation, in postmortem brain tissues from patients with AD and brain tissues from APP, APP/PS1 and 3XTg.AD mice. Using co-immunoprecipitation and immunofluorescence analyses, for the first time, we demonstrated the physical interaction between phosphorylated tau and Drp1. Mitochondrial fission-linked GTPase activity was significantly elevated in the postmortem frontal cortex tissues from AD patients and cortical tissues from APP, APP/PS1 and 3XTg.AD mice. On the basis of these findings, we conclude that Drp1 interacts with Abeta and phosphorylated tau, likely leading to excessive mitochondrial fragmentation, and mitochondrial and synaptic deficiencies, ultimately possibly leading to neuronal damage and cognitive decline. Treatment designed to reduce the expression of Drp1, Abeta and/or phosphorylated tau may decrease the interaction between Drp1 and phosphorylated tau and the interaction between Drp1 and Abeta, conferring protection to neurons from toxic insults of excessive Drp1, Abeta and/or phosphorylated tau. |
