genetics

Gene Therapies for AD

What is nerve growth factor?

Nerve growth factor, also called NGF, is a type of neurotrophin. Neurotrophins monitor neuronal cells for abnormal stimuli that could be harmful to the nervous system. They also assist in the maintenance of function, development, survival, and death of neurons (Squire, 2009). In order to conduct studies in drug therapies for Alzheimer’s disease, we must first dig deeper in understanding the mechanisms of Alzheimer’s on the genetic level. This can also lead us to gene therapies.

Figure 1 (Choi et al., 2014)

On the chart in figure 1, three gene therapies are summarized, containing the type of cell, the gene involved, the subjects used, and the results of the trials.

According to the third treatment listed in the chart above (Figure 1), neural stem cell-expressing NGF that were transplanted into the hippocampus region of mice subjects exhibiting a symptom of cognitive deficit showed protective factors of the neurons (Choi et al., 2014).

Study: TDP-43 inhibitory peptide – (Gao et al., 2019)

TDP-43 is the TAR DNA-binding protein 43. Proteinopathy of TDP-43 has become increasingly known as a major feature of Alzheimer’s disease. In this study, the mitochondria were used to attack the TDP-43 neurotoxicity in Alzheimer’s disease induced mice. To measure cognitive and motor function in the mice after administration of the inhibitory peptide, a series of tests were used (open-field tests, muscle strength tasks, etc.). By using an inhibitory peptide for TDP-43, the major symptoms of AD, neuronal loss and behavioral abnormalities, can be reduced.

Results and Discussion:

Figure 2

The schematic model (Figure 1) shows the pathology of AD in the transgenic mice as well as the administration of the inhibitory peptide (PM1) and the following behavioral tests that measured cognition and motor function. After inducing the effects of AD in transgenic mice by augmenting TDP-43 in the mitochondria, there were mixed results:

By inhibiting the TDP-43 localization in the mitochondria, the TDP-43 proteinopathy process was reduced as well as other mitochondrial abnormalities.

Figure 3

The Aβ plaque deposition remained unchanged in older mice after administering the PM1. Figure 2 shows no difference in plaque formation between the control PM (induced AD symptoms but no treatment) and the PM1. However, there was protection against neuronal loss and gliosis. Gliosis is the destruction of glial cells, which assist in the insulation of neurons.

Improved cognition and motor functions were expressed in older mice after the administration of the PM1. Cognitive deterioration in young mice was prevented by PM1 as well.

These studies have shown the potential of gene therapy in not only reducing the progression, but also restoring deteriorated parts of the nervous system.

References:

Choi, S. S., Lee, S.-R., Kim, S. U., & Lee, H. J. (2014). Alzheimers Disease and Stem Cell

Therapy. Experimental Neurobiology, 23(1), 45. doi: 10.5607/en.2014.23.1.45

Gao, J., Wang, L., Gao, C., Arakawa, H., Perry, G., & Wang, X. (2019). TDP-43 inhibitory

peptide alleviates neurodegeneration and memory loss in an APP transgenic mouse model for Alzheimers disease. Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, 1866(1), 165580. doi: 10.1016/j.bbadis.2019.165580

Squire, L. R. (2009). Encyclopedia of neuroscience. Amsterdam: Elsevier, Acad. Press.