J Neurosci. 2014 Dec 3; 34(49):16207-19.

Social interaction rescues memory deficit in an animal model of Alzheimer’s disease by increasing BDNF-dependent hippocampal neurogenesis.

Hsiao YH1, Hung HC2, Chen SH3 and Gean PW1, 2

1 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

2 Institute of Basic Medical Science, National Cheng Kung University, Tainan, Taiwan

3 Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan



It has been recognized that the risk of cognitive decline during aging can be reduced if one maintains strong social connections, yet the neural events underlying this beneficial effect have not been rigorously studied. Here, we show that amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice demonstrate improvement in memory after they are cohoused with wild-type mice. The improvement was associated with increased protein and mRNA levels of BDNF in the hippocampus. Concomitantly, the number of BrdU+/NeuN+ cells in the hippocampal dentate gyrus was significantly elevated after cohousing. Methylazoxymethanol acetate, a cell proliferation blocker, markedly reduced BrdU+ and BrdU+/NeuN+ cells and abolished the effect of social interaction. Selective ablation of mitotic neurons using diphtheria toxin (DT) and a retrovirus vector encoding DT receptor abolished the beneficial effect of cohousing. Knockdown of BDNF by shRNA transfection blocked, whereas overexpression of BDNF mimicked the memory-improving effect. A tropomyosin-related kinase B agonist, 7,8-dihydroxyflavone, occluded the effect of social interaction. These results demonstrate that increased BDNF expression and neurogenesis in the hippocampus after cohousing underlie the reversal of memory deficit in APP/PS1 mice.

KEYWORDS: APP/PS1 mice; Alzheimer’s disease; BDNF; adult neurogenesis; memory decline; social interaction

PMID: 25471562



Alzheimer’s disease (AD) is a progressive neurodegenerative disease, where dementia symptoms gradually worsen over a number of years. At present, there is no definitive evidence to support that any particular treatment is effective in preventing or reversing the progression of the disease (Luchsinger and Mayeux, 2004). It is known that loneliness and/or social isolation is a risk factor for developing Alzheimer’s disease. It also has been recognized that we can lower the risk of cognitive decline and AD if we maintain strong social connections and keep mentally active as we age. Indeed, researchers found a relationship between frequent social activity and better cognitive function (Stern, 2006; Szekely et al., 2007; Paradise et al., 2009). However, the underlying mechanisms are largely unknown. In this study, we observed that APP/PS1 mice improving their memories after co-housing with wide-type (WT) mice. Interestingly, 1-month-old WT mice were more effective than 6-month-old WT mice in helping memory improvement. Further analysis revealed a linear relationship between interaction times of the helpers and memory improvement of the APP/PS1 mice suggesting that social interaction contributes to the beneficial effect of co-housing.

Preclinical and clinical studies suggest BDNF as a potential synapse repair molecule for neurodegenerative diseases (Lu et al., 2013). However, results from clinical trials using BDNF as the therapeutic agent are not promising. This could largely be attributed to its poor penetration of blood-brain barrier (BBB) and poor bioavailability and stability such that BDNF has not reached the brain at sufficient concentrations. In addition, BDNF produces divergent effects in different brain regions. For example, chronic stress reduces BDNF in area CA3 of hippocampus, while it increases BDNF in the basolateral amygdala (BLA) resulting in dendritic hypertrophy in the BLA (Lakshminarasimhan and Chattarji, 2012). Growing evidence has linked growth of dendrites and spines in the BLA to the enhancement of anxiety-like behavior (Mitra et al., 2005). Intra-VTA infusions of BDNF resulted in the development of a depression-like phenotype that is opposite of the proposed role for BDNF in the hippocampus (Eisch et al., 2003). Therefore, it is uncertain whether BDNF has been delivered to the right tissues in the brain. Moreover, BDNF causes adverse effects including weight loss, dysaesthesias and migration and/or proliferation of Schwann cells in the subpial space, all of which out weight the proposed beneficial effects (Nagahara and Tuszynski, 2011).

In this study, we provided evidence suggesting that hippocampal BDNF plays a critical role in mediating the beneficial effect of social interaction. First, APP/PS1 mice showed increase in hippocampal BDNF protein and mRNA levels after co-housing with helpers. Second, knockdown of hippocampal BDNF by transfection with Bdnf shRNA eradicated co-housing-induced reversal of cognitive decline. Third, over-expression of BDNF in the hippocampus mimicking co-housing effect induced reversal of cognitive decline in APP/PS1 mice. Finally, 7,8-DHF, a small molecule TrkB agonist, also mimicked the effect of co-housing. More importantly, the effects of 7,8-DHF and co-housing occluded each other, suggesting that the co-housing effect is mediated by the BDNF-TrkB signal pathway. Collectively, the mechanism by which social interaction ameliorated memory deficit in APP/PS1 mice was mediated through elevating hippocampal BDNF level, leading to increased neurogenesis, which in turn to regulate cognitive function. Thus, we used a natural way by increasing social interaction to achieve sufficient BDNF con­centrations at precise sites of degenerating neurons, while avoiding adverse effects caused by BDNF in other brain regions.



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