Brain-Derived Neurotrophic Factor (BDNF) and Neurodegenerative Diseases: A Promising Therapeutic Target

What Is Brain-Derived Neurotrophic Factor or BDNF?

Brain-derived neurotrophic factor (BDNF) is a protein in the brain and spinal cord made using instructions provided by the BDNF gene. This protein participates in the development, maturation (differentiation), and maintenance of nerve cells, which in turn enhances the survival of nerve cells or neurons. In the brain, cell-to-cell communication occurs at synapses, or the junctions between nerve cells, where the BDNF protein is active. Synaptic plasticity is the ability of synapses to alter and adapt over time in response to experience. Learning and memory are aided by the regulation of synaptic plasticity, which is made possible by the BDNF protein. The brain areas that regulate eating, drinking, and body weight are home to the BDNF protein, which helps regulate these processes.

Numerous neurodegenerative illnesses, including Alzheimer’s disease, multiple sclerosis (MS), Huntington's disease, and Parkinson's disease (PD), have lower levels of BDNF. In addition to its neuroprotective (preserving the function and structure of neurons) properties, BDNF is essential for maintaining energy stability. The functions of BDNF are mentioned below:

• It plays a critical role in neuro-regeneration and the prevention of neuronal death.

• It increases adult neurons' effectiveness and encourages young neurons' proliferation.

• Due to its involvement in memory formation, BDNF is important for memory function.

What Are Neurodegenerative Diseases?

Neurodegenerative disorders arise from the gradual loss of function and eventual death of nerve cells inside the brain or peripheral nervous (outside brain and spinal cord) system. While there is presently no cure for neurodegenerative diseases, some of their physical or psychological symptoms may be lessened by various therapies. However, the progression of neurodegenerative diseases cannot be slowed down. As people age, their risk of acquiring a neurodegenerative disease increases significantly. The two most commonly seen neurodegenerative conditions are Parkinson's and Alzheimer's diseases.

What Are the Clinical Implications of BDNF?

BDNF and Alzheimer’s Disease (AD):

1. Alzheimer’s disease is a kind of dementia (memory loss) that impairs thinking, behavior, and memory. Gradually, the symptoms become severe enough to get in the way of everyday chores.

2. Research indicates that decreased levels of a protein called BDNF (Brain-Derived Neurotrophic Factor) are related to Alzheimer’s disease.

3. AD is linked to the brain's accumulation of β-amyloid peptides (Aβ) and hyperphosphorylated cleaved tau microtubules. Dementia and neuronal degeneration are brought on by the development of neuritic plaques (NP) (extracellular fibrillary amyloid deposits encircled by degenerating, inflated neurites impregnated with silver), and neurofibrillary tangles (NFT) (comprised of protease-resistant and insoluble fibril that develops within the cells), which are caused by the improper processing of Aβ.

4. According to studies, BDNF is essential for the brain's processing of amyloid. BDNF's signaling modulates glutamate receptors (AMPA and NMDA), which is important for maintaining synaptic integrity and essential for memory function. BDNF has been shown to decrease Aβ formation in neural cell cultures, whereas its lack can increase Aβ levels.

5. It has also been found that genetic variations in BDNF (BDNF Val66Met polymorphism) are associated with significant memory loss (especially in the early stages of AD).

6. It has been determined that exercise raises BDNF levels by increasing its expression, especially in the hippocampal region, which enhances memory and cognitive performance.

7. Given BDNF's protective function, administering the BDNF gene or encouraging its expression through physical activity may be useful therapeutic approaches for AD patients.

BDNF and Parkinson’s Disease

1. Parkinson's disease is a neurological condition that results in unintentional or uncontrollable movements, including stiffness, shaking, and trouble balancing and coordinating. Symptoms start slowly and get worse with time. People may experience difficulties walking and talking as the condition worsens. In addition, they could experience tiredness, sleep issues, depression (feeling sad and lost), mental and behavioral disorders, and memory problems.

2. Movement and non-motor functions are both impacted by Parkinson's disease (PD). The primary pathology is the degradation of certain brain cells in the substantia nigra (produce dopamine) called dopaminergic neurons.

3. According to the studies, the presence of high BDNF levels in the substantia nigra (brain segment) aids in the survival and appropriate operation of dopaminergic neurons.

4. BDNF shields hippocampal neurons from harm brought on by inflammation or injury. This defense mechanism stops oxidative damage by utilizing certain cell signaling pathways.

5. In Parkinson's disease (PD), endoplasmic reticulum (ER) stress (happens when proteins are misfolded or not folded correctly) can lead to apoptosis (programmed cell death) of dopaminergic neurons. BDNF triggers a signaling cascade, which is TrkB (tropomyosin receptor kinase B) expression and shields neuronal cells from apoptosis,

6. Reductions in TrkB and BDNF levels are linked to mutations in the α-synuclein protein. By inhibiting the connection between α-synuclein and TrkB, BDNF can block TrkB from disintegrating.

7. There may be a connection between a person's response to long-term PD medication and their genetic makeup for BDNF. This shows that PD patients' therapy may be predicted and guided by BDNF. To completely comprehend and utilize the advantages of BDNF for the therapy of Parkinson's disease, more research is required.

What Are the Challenges and Recent Advancements in Treating Neurodegenerative Disease With BDNF?

The primary obstacle in treating neurological illnesses with brain-derived neurotrophic factor (BDNF) is its inability to effectively reach the brain at the proper dosage. Since BDNF is a protein that is difficult to administer outside of the brain, it must be administered directly into the brain. There has not been much success with injecting BDNF into the brain ventricles (interconnected brain cavities filled with cerebrospinal fluid) or cerebrospinal fluid (CSF) (provides a cushioning effect to the brain) so that it reaches the brain directly. The effects may need to be sufficiently potent for human treatment, even if adjusted to increase concentration.

Furthermore, when administered over an extended period, brain-derived neurotrophic factor (BDNF) therapy is associated with unpleasant side effects, including dysesthesia (unpleasant sensation to the skin like stinging, and burning), weight loss, and Schwann cell (regenerates and maintains the sensory and motor neurons of the peripheral nervous system) migration into the subpial region (located beneath the pia mater which is the innermost layer of the brain). The penetration of BDNF into the outer layers is responsible for these adverse outcomes.

• BDNF Protein Infusion - Clinical trials for Parkinson's disease have focused on the direct intraparenchymal delivery of BDNF by protein infusion. This approach required implanted devices to attain the best flow rates for concentration in the putamen, which plays a role in language learning, motor control, reward, cognitive processes, speech articulation, and addiction. However, tissue damage was identified by MRI (magnetic resonance imaging) scans as a disadvantage, with low flow rates failing to trigger therapeutic responses and high flow rates producing unfavorable consequences. Furthermore, in animal experiments, backflow of BDNF in the needle resulted in distribution into the cerebrospinal fluid (CSF), which damaged neurons. Improvements like deploying a catheter for uniform distribution into selected brain regions and utilizing an infusion system to prevent protein reflux are proposed to solve these problems.

• Gene Delivery Method - The gene delivery approach is believed to offer a secure and efficient means of delivering BDNF to the targeted tissue and preventing its spread to adjacent tissues. Adenoviruses have been used as a viral vector to transfer the BDNF gene into the nucleus basalis (has strong anatomic projections to limbic areas, affects neurocognition, and may be involved in the regulation of functional networks. It also plays an important role in arousal) in an attempt to treat Alzheimer's disease by gene delivery. Additionally, it has been tried as a Parkinson's disease treatment.

• Other Methods - Using substances that promote BDNF synthesis and secretion is one of the additional methods. Also, a new approach aims to improve Trkb receptor activation using agonists such as 7,8-dihydroxyflavone [156] or BDNF mimetics like LMA22A-4. Suggestions for Trkb transactivation and using agents that facilitate receptor actions, like adenosine A2A receptor agonists, have also been suggested. It is important to consider the possible influence of receptor endocytosis (receptor-mediated endocytosis uses receptor proteins that aid in transferring big particles across cell membranes), affecting the efficacy of these techniques.

Conclusion

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that uses the TrkB receptor to control its actions. It is important because it helps to form and maintain a healthy neuronal environment, which affects how the central nervous system processes information, including memory and thought. Aging and several neurodegenerative diseases have been related to decreased BDNF activation. Future research projects should thoroughly investigate the extensive contribution of BDNF in treatment techniques and its potential as a disease biomarker.