Volume 30 Issue 7 - July 1, 2016 PDF
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Social interaction with a helper rescues memory deficit in an animal model of Alzheimer’s disease by increasing BDNF-dependent hippocampal neurogenesis
Ya-Hsin Hsiao1, Hui-Chi Hung1, Shun-Hua Chen2 and Po-Wu Gean1,*
1 Department of Pharmacology, National Cheng-Kung University
2 Department of Microbiology and Immunology, National Cheng-Kung University
 
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Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which cognitive deficits gradually worsen with age. Until now, there are no effective treatments in preventing or retarding the progression of AD. We have often been told that maintain social connection with others and keep mental active can decrease the risk of developing AD, yet the underlying mechanism of the beneficial effect is not clear.

The main aim of our study was to identify whether interaction efficacy affected the progression of AD. We used amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice as an AD mouse model. We found that contextual fear memory of APP/PS1 mice was impaired after the age of 6 months. In our research, we saw an interesting finding that cohousing 6-month-old APP/PS1 mice with 1-month-old WT mice for 3 months showed best probability of memory improvement in contrast to co-housing with 3- and 6-month old WT mice (Figure 1). The beneficial effect of cohousing was contributed by social interaction (Figure 2)

As shown in working model, the improvement was associated with increased protein and mRNA levels of BDNF in the hippocampus. Concomitantly, number of BrdU+/NeuN+ cells in the hippocampal dentate gyrus was significantly elevated after co-housing. We further utilized the experiments of ablation of neurogenesis, knockdown of BDNF, overexpression of BDNF, and TrkB agonist to prove that greater BDNF-mediated neurogenesis in the hippocampus underlies reversal of memory deficit by co-housing in APP/PS1 mice.

Figure 1. Reversal of contextual memory deficit in APP/PS1 mice after cohousing with WT mice. (A) The contextual memory was impaired after the age of 6 months. (B) 6-month-old APP/PS1 mice cohoused with 1-, 3-, 6-month-old WT and APP helpers for 3 months acquired equal levels of conditioned freezing during training. (C) Contextual freezing responses of APP/PS1mice after cohousing with 1-, 3-, or 6-month-old WT and APP/PS1 helpers for 3months. (D) Control APP/PS1 mice (n = 30) had the highest contextual freezing response (45.4%). We divided the APP/PS1 mice after cohousing into two groups: unimpaired memory mice with freezing responses >45.4% and impaired memory mice with freezing responses <45.4%. Cohousing with a 1-month-old WT helper had the best beneficial effect on the memory of APP/PS1 mice.

Figure 2. The beneficial effect of cohousing is contributed by social interaction. (A) 1-month-old WT-helpers spent longer time interacting with the APP/PS1 mice than 3- and 6-month old helpers. (B) Linear relationship between the interaction times of helpers and the contextual freezing responses of 9-month-old APP/PS1 mice after cohousing. (C) Plotting interaction times between APP/PS1 and 1-month-WT helpers versus the contextual freezing responses of 9-month-old APP/PS1 mice (after cohousing) revealed a linear relationship.


Working model:

High social interaction between APP/PS1 mice and 1-month-old WT helper increases hippocampal levels of Bdnf mRNA and protein, resulting in increased neurogenesis and thereby rescuing memory deficits in APP/PS1 mice.
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