Influence of BDNF Genetic Polymorphisms in the Pathophysiology of Aging-related Diseases

Abstract

For the first time in history, most of the population has a life expectancy equal or greater than 60 years. By the year 2050, it is expected that the world population in that age range will reach 2000 million, an increase of 900 million with respect to 2015, which poses new challenges for health systems. In this way, it is relevant to analyze the most common diseases associated with the aging process, namely Alzheimerś disease, Parkinson Disease and Type II Diabetes, some of which may have a common genetic component that can be detected before manifesting, in order to delay their progress. Genetic inheritance and epigenetics are factors that could be linked in the development of these pathologies. Some researchers indicate that the BDNF gene is a common factor of these diseases, and apparently some of its polymorphisms favor the progression of them. In this regard, alterations in the level of BDNF expression and secretion, due to polymorphisms, could be linked to the development and/or progression of neurodegenerative and metabolic disorders. In this review we will deepen on the different polymorphisms in the BDNF gene and their possible association with age-related pathologies, to open the possibilities of potential therapeutic targets.

New Frontiers in Neurodegeneration and Regeneration Associated with Brain-Derived Neurotrophic Factor and the rs6265 Single Nucleotide Polymorphism

“…Of the 11 exons, 9 fall within the 5’ region [ 18 ]. The BDNF mRNA transcripts that contain exons II and VII are exclusively expressed in the brain, whereas the transcripts containing exons I, IV, and V are expressed in peripheral tissue; exons VI and IX are broadly expressed [ 14 ]. BDNF transcription terminates at two polyadenylation sites within exon IX, thus giving rise to two distinct mRNA populations including short (0.35 kb) or long (2.85 kb) 3’ untranslated regions (UTR) [ 14 , 18 , 19 ].…”

“…The BDNF mRNA transcripts that contain exons II and VII are exclusively expressed in the brain, whereas the transcripts containing exons I, IV, and V are expressed in peripheral tissue; exons VI and IX are broadly expressed [ 14 ]. BDNF transcription terminates at two polyadenylation sites within exon IX, thus giving rise to two distinct mRNA populations including short (0.35 kb) or long (2.85 kb) 3’ untranslated regions (UTR) [ 14 , 18 , 19 ]. These two distinct populations have differing localizations: short UTR BDNF (exon I and IV) transcripts are found in the cell soma, whereas long UTR BDNF transcripts (exon II and IV) are trafficked to dendrites to regulate dendritic morphology and affect LTP [ 18 , 20 ].…”

“…Remarkably, more than one hundred polymorphisms have been described in the BDNF gene [ 14 , 69 ]. While many known variants exist within non-coding regions, understanding of their functional consequences remains limited.…”

“…BDNF production and signaling is critical for a vast array of neurophysiological processes including, but not limited to, neuronal survival, dendritic spine development, synaptogenesis, neurite outgrowth, neuroprotection, long-term potentiation (LTP), and long-term depression (LTD) (for review [ 6 , 9 , 10 , 11 , 12 ]). BDNF has also been found to be a necessary factor in neurogenesis and osteogenesis in human bone both in vitro and in vivo [ 13 , 14 ].…”

Brain-Derived Neurotrophic Factor Signaling in the Pathophysiology of Alzheimer’s Disease: Beneficial Effects of Flavonoids for Neuroprotection

“…The BDNF gene carries more than 100 polymorphisms, which may influence BDNF signaling and the pathophysiology of AD [ 47 ]. The single nucleotide polymorphism rs6265, also known as the Val66Met polymorphism, is one of the most characterized polymorphism in relation to BDNF function and risk of brain disease [ 47 ]. This polymorphism leads to valine (Val) to methionine (Met) substitution at position 66 in the prodomain of the BDNF .…”