| First Author | Calkins MJ | Year | 2011 |
| Journal | Hum Mol Genet | Volume | 20 |
| Issue | 23 | Pages | 4515-29 |
| PubMed ID | 21873260 | Mgi Jnum | J:296286 |
| Mgi Id | MGI:6459324 | Doi | 10.1093/hmg/ddr381 |
| Citation | Calkins MJ, et al. (2011) Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. Hum Mol Genet 20(23):4515-29 |
| abstractText | Increasing evidence suggests that the accumulation of amyloid beta (Abeta) in synapses and synaptic mitochondria causes synaptic mitochondrial failure and synaptic degeneration in Alzheimer's disease (AD). The purpose of this study was to better understand the effects of Abeta in mitochondrial activity and synaptic alterations in neurons from a mouse model of AD. Using primary neurons from a well-characterized Abeta precursor protein transgenic (AbetaPP) mouse model (Tg2576 mouse line), for the first time, we studied mitochondrial activity, including axonal transport of mitochondria, mitochondrial dynamics, morphology and function. Further, we also studied the nature of Abeta-induced synaptic alterations, and cell death in primary neurons from Tg2576 mice, and we sought to determine whether the mitochondria-targeted antioxidant SS31 could mitigate the effects of oligomeric Abeta. We found significantly decreased anterograde mitochondrial movement, increased mitochondrial fission and decreased fusion, abnormal mitochondrial and synaptic proteins and defective mitochondrial function in primary neurons from AbetaPP mice compared with wild-type (WT) neurons. Transmission electron microscopy revealed a large number of small mitochondria and structurally damaged mitochondria, with broken cristae in AbetaPP primary neurons. We also found an increased accumulation of oligomeric Abeta and increased apoptotic neuronal death in the primary neurons from the AbetaPP mice relative to the WT neurons. Our results revealed an accumulation of intraneuronal oligomeric Abeta, leading to mitochondrial and synaptic deficiencies, and ultimately causing neurodegeneration in AbetaPP cultures. However, we found that the mitochondria-targeted antioxidant SS31 restored mitochondrial transport and synaptic viability, and decreased the percentage of defective mitochondria, indicating that SS31 protects mitochondria and synapses from Abeta toxicity. |
