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Background

Brain-derived neurotrophic factor, or BDNF for short, is a protein in humans that is expressed primarily in areas of the brain such as the hippocampus, basal forebrain, hypothalamus, brainstem, and spinal cord ^[1]. It is also expressed in the lungs, heart, spleen, gastrointestinal tract, liver, fibroblasts, and vascular tissue ^[1]. The protein is encoded by the BDNF gene located on human chromosome 11 ^[2]. It belongs to the family of neurotrophins, which in general, are proteins that are important in neuronal survival, development, function, and brain plasticity. It was first expected to only be responsible for neurogenesis—the growth and development of new neurons within the central nervous system ^[3]. However, it’s now widely believed that the main function is to regulate synaptic plasticity (Martinowich, 2007). Synaptic plasticity is induced during memory formation and is necessary for information storage, so BDNF is important in learning, memory, and higher thinking ^[4]. BDNF is synthesized in the endoplasmic reticulum ^[1]. It then moves through the Golgi and trans-Golgi network and is cleaved by a protein convertase enzyme to form the biologically active form of the protein that gets sent into secretory vesicles ^[1]. Vesicles bind to carboxypeptidase E, an enzyme responsible for the biosynthesis of the protein. Mice have been studied to examine when a disruption in this binding occurs. When there is a disruption in this binding, the ability for cells to sort BDNF greatly decreases. Mice that are born with this problem have significant neuron loss that results in problems affecting balance and coordination, breathing, hearing, and even death, suggesting the protein's role in normal neuronal development ^[5]. Many studies have linked BDNF with multiple neurological diseases. Some of these include depression, Alzheimer’s disease, Huntington’s disease, and multiple sclerosis. In neurodegenerative diseases, BDNF levels are decreased. In addition to its neurological effects, BDNF plays a large role in homeostasis, specifically energy intake and body weight. Studies have also shown that physical activity can increase levels of brain BDNF. The positive benefits that exercise has on brain health and function are primarily due to optimizing BDNF levels, particularly in the hippocampus (Phillips, 2017). Rodents exposed to physical activity five days a week for four weeks demonstrate an increase in BDNF synthesis and release (Phillips, 2017). In addition, exercise that includes endurance training induces the expression of muscle-derived proteins that upregulate BDNF expression.

Structure

Brain-derived neurotrophic factor is a relatively small protein, only 27.48 kDa, made of 119 amino acid residues ^[6]. The secondary structure of the protein is primarily beta-sheets with only a small number of alpha-helices ^[6]. The protein is a non-covalently linked heterodimer and has close structural homology to nerve growth factor (NGF) proteins ^[2]. BDNF contains a cysteine knot motif, indicating its importance in neurogenesis. There are a few single-nucleotide polymorphisms (SNPs) of BDNF. The most commonly studied one is Val66Met and is exclusive to humans. This point mutation occurs at position 196 (or amino acid residue 66) and mutates a guanine to adenine. Upon transcription, this mutation causes an amino acid switch of valine to methionine. This polymorphism plays a role in destabilizing the mRNA transcript, leading to premature degradation ^[7]. The protein that is able to be translated is not trafficked or secreted sufficiently. It can potentially alter protein-protein interactions, binding affinities, localisation, or conformational stability of the protein (Nociti, 2020). Those with this deficit show a decline in short-term episodic memory along with abnormal activity in the hippocampus (Martinowich, 2007). This mutation is also associated with major depressive disorder (Martinowich, 2007).

Functions

Neurogenesis
The earliest studies of BDNF exhibited its role in neurogenesis, which is the growth and survival of neurons. It has been reported that exogenous application of BDNF increased dendrite length of axons as well as the complexity of neurons during the development of the visual cortex ^[1]. The inhibition of spontaneous electrical activity prevented any increase in dendritic growth elicited by exogenous BDNF, which indicates that neurons have to be active to respond to BDNF and its growth-promoting capabilities ^[1]. Using rats, studies have shown that an injection of BDNF enhanced the survival of neurons. Neurogenesis, specifically in the hypothalamus, was enhanced with continuous administration of BDNF ^[1].
Synaptic Plasticity
The hippocampus appears to be one of the most important areas of BDNF production and activity. This area of the brain is responsible for long-term memory and learning as it is an area that contains many plasticity-related molecules ^[8]. Knockout mice have shown a decline in spatial learning as induced BDNF expression in the hippocampus during contextual learning has been indicated ^[8]. Synaptic plasticity dysfunction is associated with worse performance in cognitive tasks in humans ^[9].
Lipid Metabolism
More recently, it has been reported that intracerebroventricular administration of BDNF has an impact on energy metabolism. This method of injecting the protein directly into cerebrospinal fluid allows for higher concentrations of the protein to enter the central canal of the brain. Doing this has shown a decrease in energy intake and a reduction of body weight in rats ^[1]. There is also a positive correlation between BDNF and low-density lipid (LDL) cholesterol, total cholesterol, and triglycerides ^[1]. Animals with induced diabetes were treated with BDNF and showed a reduction in blood plasma glucose levels and liver weight, as well as an increase in beta oxidation of fatty acids. Obesity and insulin resistance were found to occur with reduced BDNF levels in gene knockout mice. These results suggest that BDNF levels reflect energy homeostasis and the gene may play a role in Type 2 Diabetes ^[1].
Type 2 Diabetes
The role of BDNF in Type 2 Diabetes has been studied in both mice and humans. Administration of BDNF in obese, non-insulin-dependent mice revealed a decrease in their blood glucose levels. This continuous administration of BDNF was found to improve blood glucose control, which continued even after stopping BDNF treatment ^[1]. Further studies support that BDNF can also restore systemic blood glucose levels by significantly reducing hemoglobin A1C levels. Other evidence shows that the sympathetic nervous system is acitvated by the protein, thus indicating that energy expenditure in obese, diabetic animals is regulated as well. Intracerebroventricular administration of the protein lowered glucose levels, increased insulin production, thermogenesis, and norepinephrine turnover, which supports the previous statement ^[1].

Role in Diseases

Depression
Glucocorticoid levels are elevated during stress. Prolonged exposure to stressors and continual glucocorticoid levels reduce BDNF levels and the rate of neurogenesis. Proliferation and survival of new neurons in the hippocampus is essential for those who suffer from major depressive disorder. In addition, the levels of BDNF have been shown to be reduced in the hippocampus in anxiety and depressive disorders (Martinowich, 2007). These two processes co-occur and can lead to depression. Fortunately, antidepressant-like effects have been seen from direct infusion of BDNF into the hippocampus. Rodents with over-expression of BDNF have shown increased resilience to depression-related symptoms. Additional studies have shown that long-term administration of antidepressants, such as fluoxetine and sertraline, increase mRNA in the hippocampus, thus increasing BDNF levels and neurogenesis.
Alzheimer’s Disease
Decreased mRNA and protein levels of BDNF have been examined in AD patients. Some evidence has shown that amyloid-β protein plays a direct role in inhibiting the formation of BDNF, reducing its levels in the brain (Tanila, 2017). In an Alzheimer’s Disease brain, abnormal amyloid-β protein levels occur and clump together to form plaques. The direct connections between BDNF and Alzheimer’s Disease are still unclear, however, the formation of plaques may greatly decrease the formation of BDNF.
Multiple Sclerosis
Multiple sclerosis is an autoimmune, neurodegenerative disease of the central nervous system. The pathophysiology of this disease is due to the altered interactions between immune cells and cells of the central nervous system, leading to an uncontrolled inflammatory response that damages nerve cells. A possible mechanism of the neurodegeneration may be due to the release of BDNF by immune cells, as well as glial cells and astrocytes, two cell types of the central nervous system (Nociti, 2020). Specifically, CD4+ and CD8+ T lymphocytes, B lymphocytes, and monocytes can produce BDNF (Nociti, 2020). These immune cells in actively demyelinating areas of MS lesions overexpress BDNF (Nociti, 2020). Neurotrophin receptors that are expressed in immune cells can be targeted by paracrine neurotrophin actions, so neurotrophins, like BDNF, can mediate crosstalk between the nervous and immune systems. As of 2020, a better understanding of the interaction between BDNF and neuroinflammation is needed in order to improve the knowledge of pathogenesis and in developing therapeutics for CNS diseases (Nociti, 2020).

Clinical Significance

Brain-derived neurotrophic factor appears to contribute to many systems and processes within the human body. Its role in neurodegenerative and neuropsychiatric disorders appears to be very promising, as additional research needs to be done. A decrease in protein expression is seen in many neurological disorders such as Alzheimer’s Disease, as detailed above, as well as Parkinson’s Disease and Huntington’s Disease. Physical exercise, especially endurance training, increases BDNF levels, improving symptoms related to depression. BDNF appears to potentially prevent Type 2 Diabetes due to its role in energy intake and body weight. However, therapeutic approaches regarding BDNF and Type 2 Diabetes prevention and management remain uncertain. Further studies that examine other neurotrophins on their metabolic effects, synaptic plasticity, and neural survival are crucial to understand the pathogenesis of BDNF in depth.

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