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Monday, December 10, 2018

Using Bees to Cure Disease


From the paper: Bee venom phospholipase A2 ameliorates Alzheimer’s disease pathology in Aß vaccination treatment without inducing neuro-inflammation in a 3xTg-AD mouse model (Baek et al., 2018)

Alzheimer’s disease (AD) provokes memory loss and other neurodegenerative effects in patients and is the 6th leading cause of death in the United States (Alzheimer’s Association, n.d.). It’s caused by the buildup of two proteins – amyloid-ß (Aß) and tau proteins – which cause nervous system tissue to become inflamed (Alzheimer’s Association, n.d.; Baek et al., 2018). Most current treatment options manage symptoms of the disease, but recent research has been focused on turning to the Aß pathway as a means of slowing down or stopping AD progression (Baek et al., 2018). There have been some attempts to vaccinate mice against AD, but about 6% developed meningoencephalitis (Gilman et al., 2005), a condition in which the brain and tissues become inflamed. Researchers believe this response is caused by T cells, so they want to induce regulatory T cells (Tregs), which work to stop T cell responses from occurring (Baek et al., 2018). The researchers previously found that Tregs play a role in AD progression (Baek et al., 2016) and the compound bee venom phospholipase A2 (bvPLA2) may help stop AD progression (Ye et al., 2016). This is because bvPLA2 can promote Treg differentiation, leading to a regression of some neurological diseases (Chung et al., 2015).

The main purpose of the study was to see if bvPLA2 would induce Tregs, thus reducing AD progression without the inflammatory effects the vaccine was causing. To accomplish this, the researchers first looked at the effect of bvPLA2 on nervous tissue inflammation. In order to increase T cell response against Aß, they injected mice with Aß1-42 peptide and later boosted it twice with pertussis toxin (PT), as the toxin can help induce nervous tissue inflammation in mice (Baek et al., 2018). While mice immunized solely with Aß were fine, those treated with Aß+PT saw a survival rate that decreased by 60%. However, mice that were treated with Aß +PT+bvPLA2 saw the same high survival rate at the only Aß mice (Baek et al., 2018). The researchers also looked at how certain inflammatory cells infiltrated and aggregates in brain and spinal cord tissues (Baek et al., 2018). They found that Aß+PT mice saw high inflammatory infiltration and aggregates while Aß +PT+bvPLA2 did not (Table 1). These results suggest that bvPLA2 treatment induces Tregs, which suppress certain inflammatory cells associated with the vaccination-induced neuro-inflammation (Baek et al., 2018).


Table 1. Disease features of C57BL/6 mouse groups immunized with amyloid-ß with or without PT (Baek et al., 2018).
Next, the researchers wanted to see the effects of bvPLA2 in mice undergoing Aß vaccination therapy. They immunized mice with the Aß1-42 peptide and also injected some with bvPLA2 (Baek et al., 2018). The mice used were 3xTgAD mice, a strain with mutations related to the mice version of AD (ALZFORUM, 2018). The researchers placed the mice in a circular pool and measured how long it took them to find a hidden door and escape in order to look at spatial learning and memory (Baek et al., 2018). 3xTgAD mice took longer to escape than 3xTgAD/Aß+bvPLA2 and wildtype (WT) mice, which had similar times. Additionally, the 3xTgAD/Aß+bvPLA2 mice traveled more to the location the hidden platform was previously placed in and spent more time in the target quadrant than 3xTgAD/Aß mice (Baek et al., 2018). These data suggest that bvPLA2 helps reverse the memory loss in Aß-vaccinated 3xTgAD mice (Baek et al., 2018).


The researchers also compared the Tregs and cytokines between the different mice. In terms of Tregs, they found that the proportion of Tregs significantly increased (from 3xTgAD levels) after vaccination (Figure 4b). There was no significant difference between 3xTgAD/Aß, 3xTgAd/Aß+bvPLA2, and 3xTgAD/bvPLA2 groups (Figure 4b). For the cytokines, the researchers found that 3xTgAD mice had higher levels of inflammatory cytokines than WT mice, and mice with bvPLA2 had lower levels of some inflammatory cytokines than 3xTgAD mice (Figure 4c, 4d, 4e). The researchers also looked at the cytokine IL-10, which is produced by Tregs (Baek et al, 2018). They found that IL-10 levels were higher in bvPLA2 mice (Figure 4f), which suggests Tregs are induced in the bvPLA2 treatment.

Figure 4. Effects of bvPLA2 treatment on Tregs, inflammatory cytokine production, and serum anti-Aβ antibody levels in Aβ-vaccinated 3xTg-AD mice b, Percentages of CD4+CD25+Foxp3+cells. c, IL-2, d, IFN-γ, e, TNF-α, and f, IL-10 were measured using the CBA mouse T1/2/17 cytokine kit. **P < 0.01 and ***P < 0.001 vs. WT; #P < 0.05, ##P < 0.01, and ###P < 0.001 vs. 3xTgAD; ns: not significant (Baek et al., 2018).
Furthermore, the researchers wanted to see if antibody production is directed against Aß. They found 3xTAD mice don’t spontaneously generate antibodies reactive to Aß. The results also indicate that bvPLA2 treatment doesn’t influence Aß-specific antibody production (Baek et al., 2018). Additionally, the researchers looked at some neurological effects of bvPLA2 administration. They found, among other things, that the compound enhances glucose uptake in the brain (Baek et al., 2018). Finally, the researchers looked at if Treg depletion affected spatial learning and memory; however, I had difficulty understanding their findings (Baek et al., 2018).

All in all, the data supports the hypothesis that adding bvPLA2 in the Aß vaccination may help reduce related nervous tissue inflammation reaction. Aß vaccinated group had increased Treg populations. Overall, the researchers found that the Tregs induced by bvPLA2 secrete IL-10, which suppress other immune cells (Baek et al., 2018). The findings of the paper are important for AD research. Using bvPLA2 for Treg modification may be helpful in treatment of AD. In vaccines targeting the Aß pathway, makers may have to add some bvPLA2 for immune suppression. The more we understand the Aß pathway and nervous tissue inflammation inhibition, the closer we become to developing a cure for AD, and potentially other neuro-degenerative diseases. In terms of further researcher, I would like to know if the same sorts of effects occur in humans. Would humans even develop nervous tissue inflammation as a result of a vaccine targeting the Aß pathway in the first place? If so, would bvPLA2 help reduce it? I know vaccine trials on humans is a long way off, but I can’t help but wonder if mice are a good model for AD-related vaccines.

Works Cited
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https://www.alzforum.org/research-models/3xtg
Alzheimer’s Association (n.d.). What is Alzheimer’s? Retrieved from:
https://www.alz.org/alzheimers-dementia/what-is-alzheimers
Baek, H., Lee, C., Choi, D. B., Kim., N., Kim, Y., Ye, Y. J., Kim, Y., Kim, J. S., Shim, I., & Bae, H.
(2018). Bee venom phospholipase A2 ameliorates Alzheimer’s disease pathology in Aß vaccination treatment without inducing neuro-inflammation in a 3xg-AD mouse model. Science Reports 8:17369
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Ye, M., Chung, H., Lee, C., Yoon, M. S., Yu, A. R., Kim, J. S., Hwang, D., Shim, I., & Bae, H. 
(2016). Neuroprotective effects of bee venom phospholipase A2 in the 3xTg AD mouse model of Alzheimer’s disease. Journal of Neuroinflammation 13, 10

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