Brain-derived neurotrophic factor (BDNF) and some open questions for research

Rubiks Cube Brain Sculpt (Credit: freeny/Deviantart)

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and has been found to be related to synaptic regulation in humans. It can be used for the development of disease-modifying drugs for neurodegenerative diseases such as Alzheimer’s disease.

This article is gives some ideas for research for the treatment of neurodegenerative disorders.

Some open questions by researchers related to BDNF are as follows:

First, the vast majority of studies published so far compared BDNFVal/Val carriers with BDNFMet carriers, owing to the rarity of BDNFMet/Met homozygotes in Caucasian individuals. Gene dosage studies, by comparing all three genotypes (BDNFVal/Val, BDNFVal/Met and BDNFMet/Met), would reveal whether the phenotypic effects are truly associated with the BDNF polymorphism. The high occurrence of BDNFMet/Met in Asian populations may offer an opportunity for such studies.

Second, it is imperative to quantitatively measure the effect of the BDNF genotype on several endophenotypes: for example, hippocampal volume or cognition in the same subjects. Assuming that an alteration in BDNF trafficking or secretion correlates with changes in synaptic function, such a study will provide the most sensitive and reliable measure for synaptic changes to be used in clinical trials.

Third, studying possible epistasis between the BDNFVal/Met genotype and other common polymorphisms may offer insights into disease risk and progression that may not be revealed by assessing the effect of one single-nucleotide polymorphism alone. This could be powerful when the effects of interactions with a disease-risk gene (for example, the gene encoding apolipoprotein E4) on endophenotypes relevant to a disease (for example, episodic memory or hippocampal volume in Alzheimer’s disease) are examined.

Fourth, most studies published so far have revealed negative effects of the BDNFMet allele on brain functions. Given that the BDNF Val66Met polymorphism has been selected during evolution, it may have some beneficial effects. For example, the Met allele appears to be protective against grey matter damage in multiple sclerosis, childhood-onset bipolar disorder and obsessive compulsive disorder.

Last, differences in cognitive functions associated with the BDNF Val66Met polymorphism in adults may result from cumulative changes during decades of brain development or result from functional changes in synapses and neuronal circuitry. It is widely believed that developmental alterations of neuronal networks may be difficult to restore by pharmacological intervention; however, when the neuronal circuits formed during development remain unaltered, functional modulation of synapses can be used to restore network function. Pharmacological interventions that increase BDNF expression or secretion will not only help to distinguish these possibilities but also offer hope for therapies for diseases that result from synaptic dysfunction.

Whether antidepressants have a potential impact on the synaptic growth through BDNF–TRKB pathway or not needs further research.

Donepezil and galantamine, the acetylcholinesterase inhibitors, which are used for the treatment of cognitive deficits in early AD and mild cognitive defects, increase serum BDNF levels but it is unclear whether these drugs increase BDNF levels in brain or not.

Reference:

BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases (2013). Bai Lu, Guhan Nagappan, Xiaoming Guan, Pradeep J. Nathan & Paul Wren Nature Reviews Neuroscience DOI: 10.1038/nrn3505

Usman Zafar Paracha

Usman Zafar Paracha is a sort of entrepreneur. He is the author of "Color Atlas of Statistics", and the owner of an Android game "Faily Rocket."

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