S100B’s Trophic and Toxic Effects on Neural Cells in Relation to Alzheimer’s Disease
Author: Aditi Doiphode
Peer Reviewer: Fiona Pollack
Professional Reviewer: Sidra Tul Muntaha
Serum 100B (S100B) is a calcium-binding protein that regulates the cell cycle, cell progression and cell differentiation. Recent advances in research have shown that S100B is closely related with neural health in both trophic and toxic ways. Increased S100B levels have also been associated with blood brain compromise and the progression of neurodegenerative diseases. This review serves to compare the beneficial and harmful effects of S100B and relate its function to the blood brain barrier with a focus on Alzheimer’s disease. The purpose of this paper is to conclude recent research analyzing S100B’s effects on the progression of Alzheimer’s disease and provide a guide for future inquiries.
S100B, a member of the S100 family, is a calcium-binding protein with a molecular weight of 21 kDA. Its protein configuration includes two monomers with disulfide bonds in a double axis of rotation. S100B is expressed in various cell types throughout the body, but is most abundantly produced by astrocytes in neural and glial cells. In Schwann cells and microglia, the protein demonstrates both paracrine and autocrine effects (Daneman et al., 2015). Elevated levels of S100B have been shown to correlate with pathological disorders affecting the central nervous system due to the protein’s effect on the blood brain barrier (Yardan et al., 2011). In recent years, there has been an increased interest in S100B’s clinical application for Alzheimer’s disease, traumatic brain injury, and Down Syndrome. The blood brain is a highly specialized semipermeable border that separates the neural cells in the brain from circulatory cells in the blood. Researchers have begun to consider protein S100B’s role in blood brain barrier integrity and its effect on the progression of neurodegenerative diseases. An increase in S100B levels has also been correlated to acute stage Alzheimer’s disease (Kleindienst et al., 2007). This review aims to provide a summary of current literature of S100B’s effect in neural cells in relation to neurodegenerative diseases.
Trophic Effects of S100B
To determine the effects of S100B in the brain, the effects of the protein on the neural cells have to be understood. In one study, S100B knockout (KO) mice were compared to mice with S100B wild type mice to understand the significance of the protein. When blood brain barrier compromise was induced in S100B KO mice, it was discovered that mice without S100B developed increased blood brain barrier permeability than mice with S100B. This compromise allowed dangerous antigens, such as amyloid beta, to access the brain. When the blood brain barrier of the S100B KO mice were subsequently inspected, researchers observed that the tight junctions were discontinued and flattened (Wu et al., 2016). This finding supports the claim that S100B is necessary to maintain the tight junctions of the blood brain barrier, since the mice without the S100B experienced greater blood brain barrier dysfunction.
Additionally, experimental findings provide evidence for the trophic effects of S100B. S100B has been proven to stimulate neurogenesis, or the production of neurons (Donato et al., 2001). It also promoted cell survival, by promoting healing processes in injured neurons with interactions between neurons and growth factors (Marenholz et al., 2004). These discoveries justify S100B’s role in improving neuron production and functional recovery (Kleindienst et al., 2005). In fact, increased S100B levels have been shown to improve long-term memory. When rat models received S100B infusions, they demonstrated greater retention rates than the control group (Kleindienst et al., 2007). These results suggest that S100B may benefit the function of the hippocampus, a brain region associated with memory. However, it is important to understand that association does not imply causation. Researchers argue that while S100B may be associated with these benefits, this research does not prove that the protein solely caused them. S100B may be an unrelated factor that does not produce these effects directly (Kleindienst et al., 2010).
Moreover, S100B has been proven to decrease apoptosis frequency through activation of several cell receptors and the prevention of mitochondrial dysfunction due to glucose deprivation (Selinfreund et al., 1991). Ongoing research has found that several steps occur on a molecular level for S100B to prevent apoptosis. First, S100B binds to the receptor of glycation end products (RAGE). When it binds to RAGE, it activates the receptor and RAGE begins to respond. When RAGE is activated by S100B, the NF-kB pathway is activated and the protein Bcl-2 is produced. Bcl-2 is a protein that prevents apoptosis. Increased levels of Bcl-2 prevent cell death and promote cell survival (Businaro et al., 2006).
Toxic Effects of S100B
Although S100B has been associated with many beneficial effects, S100B has been associated with many toxic effects as well. When the central nervous system does not receive enough oxygen, glucose, or serum, the glial cells produce S100B. The produced S100B binds with RAGE, causing a dangerous elevation of reactive oxygen species, cytochrome C release, and caspase cascade activation and inducing apoptosis (Sen et al., 2007). In addition, increased levels of S100B can lead to brain inflammation. S100B expresses proinflammatory cytokines with the activation of microglia, astrocytes, and neurons (Nagele et al., 2011). Chronic inflammation can lead to permanent neurological damage or cell death.
Despite the fact that S100B promotes long term memory retention, it can also aggravate memory loss. In one study, when artificial copies of the S100B genes were introduced to young mice models, the mice experienced spatial learning impairment and behavioral rigidity. The administered S100B caused hippocampal dysfunction (Yardan et al., 2011).
So, the question arises: How can S100B be both beneficial and detrimental to neural cells? Recent research suggests that the detrimental or beneficial effects of the protein are determined by the concentration of S100B levels. When S100B is present in micromolar amounts, the protein is more likely to have negative effects on neural cells, such as hippocampal dysfunction, inflammation, and cell death (Sen et al., 2007). On the other hand, when S100B is present in nanomolar amounts, the protein is more likely to have positive effects on neural cells, such as memory retention, blood brain barrier maintenance, and cell survival (Kleindienst et al., 2007).
S100B & Blood Brain Barrier
It has been demonstrated that S100B function is essential for the maintenance of an intact blood brain barrier (BBB) in mice. Breaches in the BBB are associated with the onset of Alzheimer’s disease. (Ballabh et al., 2004). This barrier is formed by endothelial cells, or cells that line the interior of blood vessels, and is held together by tight junctions (Wilson et al., 2002). The tight junctions create a high-resistance barrier which regulates nutrient transport and the removal of waste from the central nervous system to the blood (Daneman et al., 2015). Supporting cells, such as astrocytes and pericytes, help maintain the blood brain barrier. The decreased resistance of the barrier disrupts the homeostasis of the central nervous system, allowing toxins and antigens to enter the central nervous system and the alterance of waste-clearance pathways (Erikson et al., 2013).
On an intracellular level, S100B contributes to astrocyte activation when the blood brain barrier is compromised. Using neural pathways, it guides astrocytes to the injured areas to reform the endothelial cells using the PI3K signaling pathway (Sorci et al., 2010). The implanted astrocytes are then able to stabilize the tight junctions and prevent further impairment of the blood brain barrier. Thus, astrocytes have a major influence on maintaining the blood brain barrier by repairing its tight junctions (Abbott et al., 2002). Data indicates that S100B may be necessary to exhibit this astrocytic influence when the blood brain barrier is impaired.
On an extracellular level, nanomolar concentrations of S100B bind to RAGE, producing protein Bcl-2 and promoting cell survival (Huttunen et al., 2000). Moreover, S100B activation of RAGE leads to factor-?B (NF-?B) activation in endothelial cells. The NF-?B signaling pathway has been reported to determine endothelial permeability (Wang et al., 2017). Therefore, extracellular S100B activation of RAGE and the NF-?B may be necessary to regulate endothelial cell permeability which make up the blood brain barrier.
S100B & Alzheimer’s Disease
An increase in S100B levels has been associated with acute stage Alzheimer’s disease. When the blood brain barrier is normally functioning, amyloid beta circulates from the blood to the brain by the receptor for advanced glycation endproducts (RAGE). Apolipoprotein E (ApoE) and Lipoprotein receptor-related proteins (LRP) transport this amyloid beta back from the blood to the brain (Daneman et al., 2015). However, when the blood brain barrier is compromised, the amyloid beta is not properly circulated by the blood brain barrier. It enters the brain and binds to the astrocyte cells, forming amyloid beta plaque in the brain. These amyloid beta plaques are a marker of Alzheimer’s progression. With increased amyloid beta plaques and autoantibody responses, the astrocytes stimulate an increased production of the protein S100B (Peña et al., 1995). The increase of S100B production in brain cells after formation of amyloid plaque buildup suggests its use as a possible indicator of blood brain barrier permeability and acute stage Alzheimer’s disease.
Potential Uses & Applications
S100B levels have been observed to increase in severe phases of brain damage on a molecular level. This occurs before major changes in brain composition have developed, distinguishing the protein as a possible diagnostic tool to assess blood brain barrier permeability and act as a biomarker for central nervous system injuries (Czeisler et al., 2006). In other words, S100B has the potential to determine the presence of neurodegenerative diseases or traumatic brain injury. Moreover, it can determine the viability of a treatment or predict the development of a disease.
S100B should be considered as a possible target of drug therapy for neurodegenerative diseases, specifically Alzheimer’s disease. Amplifying the effects of S100B could be useful in preventing blood brain barrier compromise and increased autoantibodies. Moreover, the autoantibody profile can be used as a diagnostic tool to determine the progression of Alzheimer’s disease in relation to blood brain barrier breach. With an increased number of autoantibodies, it can be assumed that the blood brain barrier has become increasingly compromised. The correlation between increased S100B and blood brain permeability is not just limited to Alzheimer’s disease. It can apply to many neurological illnesses involving the blood brain barrier, such as Down Syndrome, epilepsy, and traumatic brain injury. The many conditions affected by this association demonstrates its significance in this field of study.
Gaps in Professional Understanding
While the structure of S100B is well known, the function of the protein in brain cells remains inconclusive. The lack of substantiated information leads us to question: how does S100B affect blood brain barrier dysfunction? Are these effects specific to certain areas in the brain?
A major gap remains in the understanding of S100B function in neural cells. Moreover, it is unknown how the protein’s effects change from neurotoxic, inducing apoptosis and deteriorating the blood brain barrier, to neurotrophic, preventing apoptosis. To bridge these gaps in understanding, close research on the protective or detrimental effects have to be conducted, before their connection is understood. Although some research has been conducted on this specific subject, the results need to be replicated and detailed under various conditions before they can be confirmed (Yardan et al., 2011).
I thank my teacher, Mr. Nicholas Wright, for constantly encouraging students to go above and beyond in their work. I would also like to thank Dr. Venkat Venkataraman, whose guidance and help made this paper possible.