Alzheimer’s disease: Breakthrough in Genetic Research

Genetic Research in Alzheimer’s Disease: What does the future hold?

There are a number of genetic factors that have been determined by research to impact upon Alzheimer’s disease (AD), including two specific proteins; ApoE4 and ApoE3. The ApoE4 protein has been identified as a significant risk factor for AD and conversely, the ApoE3 protein has been identified as neutral to AD. The difference between these two proteins is only one amino acid.

The recent study by Wang et al., published in April 2018, aimed to determine how ApoE3 and ApoE4 influences pathological signs and symptoms of AD, using human stem cell experiments. Researchers utilsed brain cells that were engineered from donated human skin cells from people with either two copies of ApoE3 gene or two copies of the ApoE4 gene. People with two copies of the ApoE4 gene have a higher risk of developing AD than a person carrying one copy of the ApoE3 gene and one copy of the ApoE4 gene.

The results of this study determined that the ApoE4 brain cells developed higher levels of the pathology related to AD which confirmed the toxic nature of the ApoE4 protein. As a result of the toxicity of this protein, cell degeneration and death was higher in the ApoE4 brain cells. In addition to this, Wang et al. (2018), also utilised genetic editing in order to change the structure and function of ApoE4 to more closely resemble that of ApoE3. The results of this process displayed decreased AD pathology and subsequently reduced brain cell degeneration.

These results have promising implications for research and clinical practice relative to AD. Firstly, it is stated by Wang et al. (2018) that similar experiments in mice do not produce the same results relative to AD pathology. Therefore, this research highlights one of the important differences between mouse and human research models and subsequently defines why clinical drug trials may be successful in mouse models and not in humans.  In addition to this, it is evident that ApoE3 protein and/or the modification of the ApoE4 protein may be a promising avenue in the treatment of AD in the future. It should be noted however, that this study is preliminary and further research should be undertaken to determine the accuracy and validity of the results.

Ilsa Bird – Sector Support Coordinator

References:

Elder, G., Gama Sosa, M., Gasperi, R., Dickstein, D. & Hof, P. (2010). Presenilin transgenic mice as models for Alzheimer’s disease. Brain Structure & Function, 214(2-3),127-43. DOI: 10.1007/s00429-009-0227-3

Schellenberg, G. & Montine, T. (2012). The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathologica, 124(3), 305-23. DOI: 10.1007/s00401-012-0996-2.

Wang, C., Najm, R., Xu, Q., Jeong, D., Walker, D. Balestra, M., … Huang, Y. (2018). Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nature Medicine, April. DOI: 10.1038/s41591-018-0004-z