The Effects of Cardiotrophin-1 on Early Synaptic Mitochondrial Dysfunction and Synaptic Pathology in APPswe/PS1dE9 Mice
Wang, D.; Liu, X.; Liu, Y.; Li, S.; Wang, C.
Journal of Alzheimer's Disease Jad 59(4): 1255-1267
2017
ISSN/ISBN: 1875-8908 PMID: 28731433 DOI: 10.3233/jad-170100
Accession: 060344567
The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cardiotrophin-1 (CT-1) has been shown to exhibit impressive neuroprotective effects. Previous studies have shown positive effects of CT-1 on brain glucose metabolism and cognition in APPswe/PS1dE9 transgenic mice; however, little is known about the effects of CT-1 on early synaptic mitochondrial dysfunction and resultant synaptic pathology in the brain. In this study, 4-month-old transgenic mice with brain tissue-specific CT-1 expression were used alone or in combination with APPswe/PS1dE9 transgenic mice to evaluate the effect of CT-1 on synaptic mitochondrial dysfunction and resultant synaptic pathology, and cryptic memory deficits in the APPswe/PS1dE9 transgenic mice. The potential mechanism of action of CT-1 was also examined. Young CT-1×APPswe/PS1dE9 transgenic mice exhibited improvements in long-term learning and memory ability and ameliorations of synaptic mitochondrial/synaptic impairments compared to young APPswe/PS1dE9 transgenic mice. Moreover, CT-1 upregulated the expression of AMPAR and increased AMP-activated protein kinase (AMPK) activity in the hippocampus of APPswe/PS1dE9 transgenic mice. However, AMPK inhibition through shRNA knockdown of AMPKα blocked the neuroprotective effects of CT-1 on the expression of AMPAR and mitochondrial/synaptic dysfunction in Aβ-treated mouse neurons. These results suggest that CT-1 may be a potent candidate for the early prevention and treatment of AD.