Clinical

Scientists eliminate key Alzheimer’s feature in animal model

Study suggests possible way to prevent memory-robbing disease

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Amyloid beta plaques in an Alzheimer’s disease mice model were eliminated by altering the biochemistry of brain cells in the study, which was conducted by scientists at the University of Texas Southwestern Medical Center. The research, which was published in the journal eLife, might one day lead to medicines that prevent people from developing the memory-robbing disease. “We believe that medications that target the same protein that we blocked in these mice might one day help prevent Alzheimer’s disease from ever occurring,” said Joachim Herz, M.D., Professor of Molecular Genetics, Neurology, and Neuroscience at the University of Texas Southwestern Medical Center. Connie Wong, a graduate student working with Dr. Herz, was the study’s co-lead author.

More over half of those with Alzheimer’s disease get it late in life, beyond the age of 65. It is known that Alzheimer’s disease is characterized by the presence of aberrant forms of proteins tau and amyloid beta in the brain cells. Apolipoprotein E4 (ApoE4) is one of three variations of a protein involved in mammalian fat metabolism, and it has long been recognized that it is a substantial genetic risk factor for late-onset Alzheimer’s disease. According to human studies, those who have an uncommon ApoE4 version live longer than those with the most prevalent ApoE3 form, which causes Alzheimer’s at a younger age. Ms. Wong said that structurally, ApoE3 and ApoE2 are extremely similar. However, ApoE3 includes one amino acid change, resulting in a higher positive charge on the protein. Two amino acid changes characterize the ApoE4 variation, which has the largest positive charge of the three ApoE protein variants. It’s unclear how these variations increase the likelihood of developing late-onset Alzheimer’s disease.

Dr. Herz, Ms. Wong, and their colleagues focused their new research on early endosomes, organelles that sort proteins, recycle them, or transport them through the cell’s interior to cellular trash dumps called lysosomes. People and animals with ApoE4 have larger early endosomes than those with the other two ApoE variations, according to previous study. Researchers found that the positive charges on ApoE4 caused the protein to cluster within early endosomes because ApoE4’s charge matched that of the environment inside endosomes in genetically engineered animals that imitate Alzheimer’s disease and generate human ApoE4 and amyloid beta. When these organelles get clumped together, they can no longer transport, recycle, or get rid of other proteins like amyloid beta that are found throughout the cell.

In brain cells, however, the deleterious effects of ApoE4 were removed when a genetic method was employed to switch off a gene called NHE6. This gene produces a protein that regulates the pH of endosomes by exchanging acidic protons for sodium ions. NHE6 Taking the NHE6 gene out of the cell made early endosomes acidic, which prevented amyloid beta formation in the lab mice that were tested. This protective effect of having ApoE2 was achieved by blocking NHE6, which Ms. Wong hopes drugs may be able to duplicate in the future.

In the future, the team intends to look at ways to block NHE6 even more. Co-lead authors Theresa Pohlkamp, now at Regeneron Pharmaceuticals, and Xunde Xian, now at Peking University, as well as Murat S. Durakoglugil, Gordon Chandler Werthmann, Bret M. Evers, Charles L. White III, Jade Connor, and Robert E. Hammer, were all former or current UTSW researchers who contributed to this study. The Riken Center for Brain Science’s Takaomi C. Saido contributed as well. National Institutes of Health grants helped fund this research, as did the Darrell K. Royal Research Fund, the BrightFocus Foundation (A20135245, A2016396S), the Harrington Discovery Institute, a Circle of Friends Pilot Synergy Grant, and the Bluefield Project to Cure FTD, among other sources. Additional funding came from the Harrington Discovery Institute and the Bluefield Project to Cure FTD.

Source: Theresa Pohlkamp, Xunde Xian, Connie H Wong, Murat S Durakoglugil, Gordon Chandler Werthmann, Takaomi C Saido, Bret M Evers, Charles L White, Jade Connor, Robert E Hammer, Joachim Herz. NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque loadeLife, 2021; 10 DOI: 10.7554/eLife.72034

Categories: Clinical