Toxicity of apolipoprotein E4 could be ameliorated


View:383 Time:2018-04-10


A new study, led by researchers from the University of California and Gladstone Institute of Neurological Disease, has now shed light on the toxicity of apolipoprotein E4 in human neurons.

Genes are one of many risk factors for Alzheimer's disease (AD), the most common cause of dementia. One of the genes that increase the risk of AD is the APOE gene. There are three types of the APOE gene, called alleles: APOE2, APOE3 and APOE4. APOE2 is the rarest form and appears to reduce the risk of AD; APOE3 is the most common and doesn't seem to affect the risk of AD; APOE4 is a little more common and appears to increase the risk of AD. Every person has two copies of each gene, one inherited from each parent. So your APOE "genotype" may be E2/E2, E2/E3, E2/E4, E3/E3, E3/E4, or E4/E4. Having one copy of APOE4 increases your risk of developing AD by 2 to 3 times while having two copies of the gene increase the risk by 12 times.

Genes control the function of every cell in your body. APOE makes a protein called apolipoprotein E (APOE), which plays central roles in lipid metabolism, neurobiology, and neurodegenerative diseases. The APOE4 protein has different structure and function compared with the APOE3 protein. Until now, however, why APOE4 causes more brain damage than APOE3 has not been fully understood. Now, a new study has thrown great light on this question. According to the corresponding author of the study, Dr. Yadong Huang from the University of California, previous AD drug development was disappointing despite years of efforts. Previous research has mainly done in mouse AD models, and many drugs tested effective in mouse models failed to work in humans. These lead scientists to question whether mouse AD models could perfectly reproduce human AD and highlight the need to develop novel AD models. Dr. Huang chose human cells to investigate AD and test candidate drugs. Using human neurons derived from induced pluripotent stem cells that expressed ApoE4, Dr. Huang's team discovered that the ApoE4 protein did not function properly and increased Aβ production in human neurons. Since Aβ accumulation is a hallmark of AD and appears to play key roles in the pathogenesis of the disease, ApoE4 indeed causes brain cell damage associated with AD. Importantly, ApoE4 did not change Aβ production in mouse neurons. This suggests that how ApoE4 affects Aβ production differs in humans and in mice.

Further experiments demonstrated that neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes. When ApoE4-expressing neurons were treated with a small-molecule structure corrector, the detrimental effects of ApoE4 were reduced, and the cell function and survival were improved.

Taken together, these data reveal the ApoE4 protein can lead to neuron damage associated with AD. It is possible to target ApoE4 to treat ApoE4-related AD.

The full paper (Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector) can be read in the journal Nature Medicine.
 
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