T cell-based delivery of BDNF to modulate Alzheimer's Disease

 

T cell-based delivery of BDNF to modulate Alzheimer's Disease 

Alzheimer's disease is a neurodegenerative progressive disorder that has become more prevalent in society today. Since it has been suggested that the development of Alzheimer’s disease can occur well before the onset of symptoms, researchers need to determine how to locate the origins of the disease early and effectively administer drugs to counteract any degeneration. Some of the hallmark pathological effects of Alzheimer’s Disease (AD) include neurotoxic inflammation, neuronal loss specifically in hippocampal and cortical neurons, an accumulation of amyloid beta-protein plaques, and imbalances in the brain-derived neurotrophic factor (BDNF). In the articles presented below, researchers focus on measuring brain-derived neurotrophic factor (BDNF) biosynthesis and signaling as it relates to Alzheimer’s disease and how BDNF delivery can effectively work to modulate the effects of AD.

In the article titled “Serum pro-BDNF levels correlate with phospho-tau staining in Alzheimer’s disease,” researchers Krishna L. Bharani, et al., examined the correlation between BDNF levels in postmortem serum and brain samples and hippocampal pathology in patients who had differing severities of AD. They also observed the relationship between TrkB, BDNF’s receptor, and AD. This is a primitive study, as researchers were able to use and measure BDNF levels in serum, cerebral spinal fluid (CSF), and brain samples from the same patients. In their findings, they discovered that “BDNF in CSF was detected at a lower ratio in the AD group than in the control group…” (Bharani, Ledreux, Gilmore, Carroll, & Granholm, 2020). These findings are supported by previous knowledge that there is an imbalance of BDNF levels in AD patients. In terms of the TrkB BDNF cognate receptor, researchers found that Alzheimer’s patients had a decreased density of these receptors in the hippocampal region. This finding further supports the idea that disruption of BDNF and its receptors are hallmarks of AD. Using these findings, researchers believe that the restoration of BDNF and its receptors in AD may ameliorate AD progression. 

In the article “BDNF-producing, amyloid B-specific CD4 T cells as targeted drug-delivery vehicles in Alzheimer’s disease,” researchers Ekaterina Eremenko, et al., attempt to reduce AD progression by administering BDNF in hopes that it will halt the degeneration of hippocampal brain areas. Since, as shown in the previous study, BDNF and TrkB receptor disruption and imbalance seem to be prevalent in AD, researchers hypothesized that intra-brain delivery of BDNF may decrease some of the effects of AD such as neurotoxic inflammation and amyloid plaque build-up. However, the delivery of BDNF poses a significant challenge, as such treatments of neurodegenerative diseases need to be able to pass through the blood-brain barrier (BBB) to be effective. Using their previous knowledge of the success of CD4 T cells migrating to AB plaques in mice, researchers “...generated AB-specific CD4 T cells, transduced them to express BDNF, and ICV-injected them into the mice to determine whether the targeted delivery of BDNF to sites of amyloid pathology can ameliorate the disease process” (Eremenko et al., 2019).  Notably, they discovered that the mice injected with these CD4 T cells, displayed higher levels of BDNF and TrkB receptors in the hippocampus than their controls. This finding solidifies the use of ICV-injection as a way to deliver drugs to the hippocampal region effectively. They also discovered that their injection increased synaptic and neuronal recovery in the hippocampus and decreased inflammation. Regarding amyloid plaque build-up, it was found that plaques were significantly reduced in the injected mice. Taken together, these findings support AB-specific CD4 T cells as a possible, viable option for the treatment of Alzheimer’s disease. 

As the first study explored the levels of BDNF in serum, CSF, and brain tissue, the second study built off of those findings to determine a way to ameliorate some of the hallmark pathologies of Alzheimer's disease. The findings presented in the second study provide hope that there may be a way to ameliorate the effects of Alzheimer’s disease on the brain. The results seem promising, as the mice that were treated displayed improvement in terms of reduced plaques and inflammation. However, before such a treatment can be used on humans, additional studies must be conducted to further explore the therapeutic capacity of T cells and what type of administration of the cells would be clinically feasible. Yet, with these studies and many other similar studies working to determine a way to ameliorate Alzheimer's effects, viable treatment options may come within the near future. 

 Citations 

Bharani, Ledreux. “Serum Pro-BDNF Levels Correlate with Phospho-Tau Staining in Alzheimer’s Disease.” Neurobiology of Aging, vol. 87, Elsevier Inc, Mar. 2020, pp. 49–59, doi:10.1016/j.neurobiolaging.2019.11.010.

Eremenko, Mittal. “BDNF-Producing, Amyloid β-Specific CD4 T Cells as Targeted Drug-Delivery Vehicles in Alzheimer’s Disease.” EBioMedicine, vol. 43, Elsevier BV, May 2019, pp. 424–34, doi:10.1016/j.ebiom.2019.04.019.