Relevance of BDNF-Associated Factors in Alzheimer's Disease and Depression

    Brain-derived neurotrophic factor, commonly referred to as BDNF, is a protein associated with processes of neuronal plasticity, specifically in the regulation of neuron survival, growth, and differentiation. It exists in two forms, pro-BDNF (precursor form) or mBDNF (mature forms), which bind to either p75NTR or TrkB receptors, respectively, and ultimately promote specific outcomes such as neuronal death or survival. Because of its influential function in regulating these processes, changes in BDNF expression or signalling have been implicated in the pathology of multiple neurodegenerative diseases and, possibly, in psychiatric disorders.

    In the article, “Serum pro-BDNF levels correlate with phospho-tau staining in Alzheimer’s disease”, Bharani et al. aim to establish a significant relationship between BDNF expression densities and pathological development of AD. Therefore, the researchers utilize immunohistochemistry and staining in order visualize the levels of expression of pro-BDNF, mBDNF, tBDNF (total), p75NTR and TrkB receptors, and other glia and proteins in the cerebrospinal fluid, hippocampus, Brodmann area 46, and entorhinal cortex of postmortem AD brains with varying degrees of disease severity. Results show that there were typically lower pro-BDNF levels in the BA46 and entorhinal cortex, but not in the hippocampus, in AD brains compared to control brains, regardless of severity. Likewise, in hippocampal brain tissue, there is a significant general decrease in staining densities for the TrkB receptors, but higher staining densities for amyloid, pTau, and GFAP-stained astrocytes in AD samples. Comparison between the AD subgroups that varied in severity further characterize the role of BDNF in AD such that the high-AD subgroup had higher staining densities of the metabolite proteins (amyloid, pTau, and GFAP staining), and lower levels of expression of tBDNF in the entorhinal cortex and hippocampus compared to the low-AD subgroup. It is worth noting that the tBDNF expression is higher in the low-AD subgroup than the high-AD subgroup which may highlight a compensatory increase when AD pathology is mild. Additionally, these AD subgroup results also provide a correlation between AD severity, inflammatory symptoms caused by a buildup of the proteins, and BDNF.

    Similarly, shifting the focus to BDNF’s involvement in psychiatric disorders, Yang et al. review various studies that potentially provide significant conclusions of the relevance of BDNF-associated factors in the pathophysiology of depression and their relationship with antidepressant drugs. They employ the neuroplasticity hypothesis which proposes that defects in the regulatory processes of plasticity such as those affecting neuronal atrophy, neuronal death, and neurogenesis are correlated with depression and attempt to link the cause of depression to BDNF and other neurotrophins. BDNF potentially participates in synaptic plasticity such that it is shown to strengthen existing mature synapses through, for example, inducing LTP (long-term potentiation) to aid in the growth of dendritic spines in the hippocampus. To discuss a few of the many studies analyzed, evidence of the role of neuroplasticity in depression is assessed in research pertaining to abnormal synaptic plasticity in stressed rodents and, separately, MDD patients which exhibited similar differences in the frontal limbic regions. These studies also reported that the depressive symptoms were reversed by ketamine, an NMDA receptor antagonist, which affected glutamate synapses. Focusing on human models, the authors referred to a study by Guilloux et al. (2012 which reported the decreased expression of BDNF and its associated receptor, TrkB in the postmortem brains of depressed individuals. To add, previous studies have also linked mutations in the BDNF gene (specifically, SNPs) to smaller hippocampal volumes in mice models, which is a potential indicator for a greater risk of depression if the individual experiences stress. This attempted to show the link between environmental and genetic factors in affecting the outcome of depression based on each individual. Moreover, discussing the effect of current pharmaceutical treatments on neurotrophic factors, they presented that previous studies have shown antidepressant drugs such as fluoxetine promote BDNF and TrkB mRNA expression and signaling in the hippocampus; however, this does not present a direct interaction with improvements in neuroplasticity, but it is possible that antidepressants could have such effects.

    Both studies demonstrate that the role of BDNF is significantly in Alzheimer's disease and depression, although the specifics of the neurotrophic factor’s involvement is not entirely identified. Since a potential correlation has been established to the pathologies of each disease, further studies on the variability of onset and depressive symptoms depending on the individual and the relationship between various origins of BDNF will most likely provide rewarding results for opportunities to use BDNF in pharmacological studies as a treatment and expand these theories to other neurodegenerative disorders such as Parkinson's or even neurological disorders such as epilepsy.

References

Bharani, K. L., Ledreux, A., Gilmore, A., Carroll, S. L., & Granholm, A. (2020). Serum pro-BDNF levels correlate with phospho-tau staining in Alzheimer's disease. Neurobiology of Aging, 87, 49-59. doi:10.1016/j.neurobiolaging.2019.11.010

Yang, T., Nie, Z., Shu, H., Kuang, Y., Chen, X., Cheng, J., . . . Liu, H. (2020). The Role of BDNF on Neural Plasticity in Depression. Frontiers in Cellular Neuroscience, 14:82. doi:10.3389/fncel.2020.00082