Alzheimer’s disease poses a health problem of pandemic proportions. It is estimated that by the year 2030 there will be greater than 60 million people worldwide with AD, and $375 billion will be spent annually in the United States to care for affected individuals. The process of drug discovery in AD is complicated by the fact that the causes and underlying mechanisms of the disease are still incompletely defined, and presymptomatic diagnosis is not yet in routine clinical use. Now, a study from researchers at the Buck Institute and UCLA offers an explanation for why a particular genetic form (allele) of apolipoprotein E (ApoE) poses the most significant genetic risk for Alzheimer’s disease. The team state that their findings cast the lipid-binding ApoE4 in an entirely new light, showing that it is a transcription factor that enters the nucleus and binds DNA with high affinity, including the promoter regions of 1700 different genes.
Previous studies show that the apolipoprotein E ε4 allele (ApoE; chromosomal locus 19q13) is the single most important genetic risk factor associated with Alzheimer’s disease. This allele confers increased risk for sporadic and familial Alzheimer’s disease. Individuals with two copies of the ApoE ε4 allele have an approximately eightfold increased risk of Alzheimer’s disease and have a significantly lower age of onset compared with Alzheimer’s disease patients not carrying this allele. Earlier studies from the group showed a connection between ApoE4 and Alzheimer’s via the anti-aging protein Sirtuin1 (SIRT1), the same molecule whose activity is enhanced by resveratrol, an ingredient in red wine. The current study shows that when the genes whose promoters bind ApoE4 are considered in functional groups, their relationship to Alzheimer’s disease is striking.
The current study used a combination of neural cell lines, skin fibroblasts from Alzheimer’s patients, and ApoE targeted mouse brains, and utilized chromatin immunoprecipitation and high-throughput DNA sequencing. Results show that the presence of ApoE4 triggered the reduction of SIRT1 both in neural cells and in the brains of Alzheimer’s patients with ApoE4. Data findings show that ApoE4 also targets genes associated with sirtuins and aging, insulin resistance, inflammation and oxidative damage, accumulation of amyloid plaques and tangled tau among others.
The lab note that how ApoE4 triggered the reduction of SirT1 was not explained in that study. They go on to add, however, that their results offer an exciting new possibility to design therapeutics that would block the coordinated action of these 1700 ApoE4-associated genes in their Alzheimer’s risk induction, and such an approach is now underway.
The team surmise that the fact that a lipoprotein in the blood is also a transcription factor that directly controls gene expression makes it an important factor across the lifespan. They go on to add that that their work may lead to a new type of screen for Alzheimer’s prevention and treatment. For the future, the researchers state they are designing and engineering novel drug candidates that target several of the ApoE4 mediated pathways simultaneously. They go on to conclude, that ultimately they want to develop a drug that can be given to ApoE4 carriers that would prevent the development of Alzheimer’s disease, and these results provide a mechanism and screen to do so.
Source: The Buck Institute