Neuroprotective effects of bee venom phospholipase A2 in the 3xTg AD mouse model of Alzheimer’s disease

Ye, Minsook; Chung, Hwan‐Suck; Lee, Chanju; Yoon, Moon Sik; Yu, A Ram; Kim, Jin Su; Hwang, Deok‐Sang; Shim, Insop; Bae, Hyunsu

doi:10.1186/s12974-016-0476-z

Cited by 64 publications

(64 citation statements)

References 65 publications

(67 reference statements)

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“…The 3×Tg mice exhibit a regional and age-dependent enhancement of F4/80-positive (Janelsins et al, 2005), IBA1-positive (Montgomery et al, 2011), and CD11b-positive microglia (Ye et al, 2016). The phenomenon is associated with amplification of various factors of inflammation in the brain, including TNFα (Montacute et al, 2017).…”

Section: Discussionmentioning

confidence: 96%

L-Norvaline, a New Therapeutic Agent against Alzheimer’s disease

Polis

Srikanth

Gurevich

et al. 2018

Preprint

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Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder with an insidious onset. The disease is characterized by cognitive impairment and a distinct pathology with neuritic plaques and neurofibrillary tangles.Growing evidence highlights the role of arginase activity in the manifestation of AD.Upregulation of arginase was shown to contribute to endothelial dysfunction, atherosclerosis, diabetes, and neurodegeneration. Regulation of arginase activity appears to be a promising approach for interfering with the pathogenesis of AD and other metabolic disorders. Therefore, the enzyme represents a novel therapeutic target.Here, we administer an arginase inhibitor L-norvaline to a mouse model of AD. Then, we evaluate the neuroprotective effect of L-norvaline using immunohistochemistry, proteomics, and quantitative polymerase chain reaction assays. Finally, we identify the biological pathways activated by the treatment.Remarkably, we find that L-norvaline treatment reverses the cognitive decline in AD mice. We show the treatment is neuroprotective as indicated by reduced betaamyloidosis, alleviated microgliosis, and TNFα transcription levels. Moreover, elevated levels of neuroplasticity related protein PSD-95 were detected in the hippocampi of mice treated with L-norvaline. Furthermore, we disclose several biological pathways, which are involved in cell survival and neuroplasticity and are activated by the treatment.Through these modes of action, L-norvaline has the potential to improve the symptoms of AD and even interfere with its pathogenesis. As such, L-norvaline is a promising neuroprotective molecule that might be tailored for the treatment of a range of neurodegenerative disorders.

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Section: Discussionmentioning

confidence: 96%

L-Norvaline, a New Therapeutic Agent against Alzheimer’s disease

Polis

Srikanth

Gurevich

et al. 2018

Preprint

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“…The therapeutic effect of bvPLA2 extends to the treatment for neurodegenerative diseases including AD [32]. Previous studies demonstrated the neuroprotective effect of bvPLA2 against Parkinson's Disease [33] and AD [9]. The main action of bvPLA2 on a cellular level is the suppression of immune responses through the stimulation of dendritic cells, which ultimately leads to an increased function of Treg cells [20].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, bvPLA2 is a potent inducer of T helper type 2 (Th2) immune reactions and the activation of group 2 innate lymphoid cells (ILC2) through the release of IL-35 [7]. Recently, numerous studies have reported the protective effects of bvPLA2 against a variety of diseases, including Alzheimer's disease, allergic asthma, and cisplatin-induced organ inflammation [8][9][10]. Chung et al revealed that bvPLA2 binds to a mannose receptor (CD206) or a C-type lectin on dendritic cells (DC) and increases the expression of prostaglandin E2 (PGE2), which binds to EP2 receptors on naïve T helper cells and leads to the differentiation into CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) [11].…”

Section: Introductionmentioning

confidence: 99%

Bee Venom Phospholipase A2 Induces Regulatory T Cell Populations by Suppressing Apoptotic Signaling Pathway

Baek

Park

et al. 2020

Toxins

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Bee venom phospholipase A2 is a lipolytic enzyme in bee venom that catalyzes hydrolysis of the sn-2 ester bond of membrane phospholipids to produce free fatty acid and lysophospholipids. Current evidence suggests that bee venom phospholipase A2 (bvPLA2) induces regulatory T cell expansion and attenuates several immune system-related diseases, including Alzheimer’s disease. The induction of Treg cells is directly mediated by binding to mannose receptors on dendritic cells. This interaction induces the PGE2-EP2 signaling pathway, which promotes Treg induction in CD4+ T cells. In this study, we investigated the effects of bvPLA2 treatment on the apoptotic signaling pathway in Treg populations. Flow cytometry was performed to identify early apoptotic cells. As a result, early apoptotic cells were dramatically decreased in bvPLA2-treated splenocytes, whereas rapamycin-treated cells showed levels of apoptotic cells similar to those of PBS-treated cells. Furthermore, bvPLA2 treatment increased expression of anti-apoptotic molecules including CTLA-4 and PD-1. The survival rate increased in bvPLA2-treated Tregs. Our findings indicate that bvPLA2-mediated modulation of apoptotic signaling is strongly associated with the Treg induction, which exhibits protective effects against various immune-related diseases. To our knowledge, this study is the first to demonstrate that bvPLA2 is the major bee venom (BV) compound capable of inducing Treg expansion through altering apoptotic signal.

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“…Consistently, transient depletion of Tregs in mouse models of AD accelerates the onset of cognitive deficits; conversely, amplification of Tregs improves cognitive functions (165). Therefore, increased frequency and suppressive activities of Tregs within AD patients suggest a protective role in autoimmune disorders (166,167).…”

Section: Amyloid β and Regulatory T Cellsmentioning

confidence: 92%

Amyloids in Site-Specific Autoimmune Reactions and Inflammatory Responses

et al. 2020

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Amyloid deposition is a histological hallmark of common human disorders including Alzheimer's disease (AD) and type 2 diabetes. Although some reports highlight that amyloid fibrils might activate the innate immunity system via pattern recognition receptors, here, we provide multiple lines of evidence for the protection by site-specific amyloid protein analogs and fibrils against autoimmune attacks: (1) strategies targeting clearance of the AD-related brain amyloid plaque induce high risk of deadly autoimmune destructions in subjects with cognitive dysfunction; (2) administration of amyloidogenic peptides with either full length or core hexapeptide structure consistently ameliorates signs of experimental autoimmune encephalomyelitis; (3) experimental autoimmune encephalomyelitis is exacerbated following genetic deletion of amyloid precursor proteins; (4) absence of islet amyloid coexists with T-cell-mediated insulitis in autoimmune diabetes and autoimmune polyendocrine syndrome; (5) use of islet amyloid polypeptide agonists rather than antagonists improves diabetes care; and (6) common suppressive signaling pathways by regulatory T cells are activated in both local and systemic amyloidosis. These findings indicate dual modulation activity mediated by amyloid protein monomers, oligomers, and fibrils to maintain immune homeostasis. The protection from autoimmune destruction by amyloid proteins offers a novel therapeutic approach to regenerative medicine for common degenerative diseases.

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Neuroprotective effects of bee venom phospholipase A2 in the 3xTg AD mouse model of Alzheimer’s disease

Cited by 64 publications

References 65 publications

L-Norvaline, a New Therapeutic Agent against Alzheimer’s disease

L-Norvaline, a New Therapeutic Agent against Alzheimer’s disease

Bee Venom Phospholipase A2 Induces Regulatory T Cell Populations by Suppressing Apoptotic Signaling Pathway

Amyloids in Site-Specific Autoimmune Reactions and Inflammatory Responses

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