Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice

• Intrahippocampal CDNF protein or gene improved long-term memory in mice.
• CDNF did not influence short-term memory, spontaneous activity or object neophobia.
• CDNF did not significantly affect brain amyloid load or adult neurogenesis.

Cerebral dopamine neurotrophic factor (CDNF) protects and repairs dopamine neurons in animal models of Parkinson's disease, which motivated us to investigate its therapeutic effect in an animal model of Alzheimer's disease (AD). We employed an established APP/PS1 mouse model of AD and gave intrahippocampal injections of CDNF protein or CDNF transgene in an AAV2 viral vector to 1-year-old animals. We performed a behavioral test battery 2 weeks after the injections and collected tissue samples after the 3-week test period. Intrahippocampal CDNF-therapy improved long-term memory in both APP/PS1 mice and wild-type controls, but did not affect spontaneous exploration, object neophobia or early stages of spatial learning. The memory improvement was not associated with decreased brain amyloid load or enhanced hippocampal neurogenesis. Intracranial CDNF treatment has beneficial effects on long-term memory and is well tolerated. The CDNF molecular mechanisms of action on memory await further studies.