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By Dana Smith / Gladstone News / April 9, 2018
Yadong Huang and his team discovered how to erase the damage in human brain cells caused by apoE4, the primary genetic risk factor for Alzheimer’s disease

Using human brain cells, scientists at the Gladstone Institutes discovered the cause of—and a potential solution for—the primary genetic risk factor for Alzheimer’s disease, a gene called apoE4.

Having one copy of the apoE4 gene more than doubles a person’s likelihood of developing Alzheimer’s disease, and having two copies of the gene increases the risk by 12-fold, as compared to the most common version of the gene, apoE3.

The apoE4 gene creates a protein of the same name. The apoE4 protein differs from the apoE3 protein at only one point, but that single change is enough to alter its main structure and, thus, its function. Scientists have been unclear about why apoE4 is so much more damaging to brain cells than other versions of the protein.

In a new study published in , researchers revealed how apoE4 confers its risk for Alzheimer’s disease in human brain cells. What’s more, they were able to erase the damage caused by apoE4 by changing it, with a small molecule, into a harmless apoE3-like version.

A Better Model

Most Alzheimer’s research and drug development are done in mouse models of the disease. However, a succession of clinical trial failures has spurred scientists to turn to other models.

“Drug development for Alzheimer’s disease has been largely a disappointment over the past 10 years,” says lead author Nike Jordan Kids Jordan Jumpman Pro BG Cool Grey/ Whitewolf Grey jbzjz60mks
a senior investigator and director of the Center for Translational Advancement at Gladstone.

“Many drugs work beautifully in a mouse model, but so far they’ve all failed in clinical trials. One concern within the field has been how poorly these mouse models really mimic human disease.”

Instead, Huang decided to use human cells to model the disease and test new drugs. Thanks to induced pluripotent stem cell technology, his team was able to examine, for the first time, the effect of apoE4 on human brain cells. To do so, the researchers created neurons from skin cells donated by Alzheimer’s patients with two copies of the apoE4 gene, as well as from healthy individuals who had two copies of the apoE3 gene.

The researchers confirmed that, in human neurons, the misshapen apoE4 protein cannot function properly and is broken down into disease-causing fragments in the cells. This process results in a number of problems commonly found in Alzheimer’s disease, including the accumulation of the protein tau and of amyloid peptides.

Notably, the presence of apoE4 does not change the production of amyloid beta in mouse neurons. But in human cells, scientists noticed apoE4 has a very clear effect on increasing amyloid beta production, which highlights the species difference in the way apoE4 controls amyloid beta metabolism.

“There’s an important species difference in the effect of apoE4 on amyloid beta,” says Chengzhong Wang, PhD, the first author on the paper and former research scientist at Gladstone. “Increased amyloid beta production is not seen in mouse neurons and could potentially explain some of the discrepancies between mice and humans regarding drug efficacy. This will be very important information for future drug development.”

Fixing a Toxic Protein

Once the scientists confirmed that apoE4 does, indeed, cause damage in human cells related to Alzheimer’s disease, a key question remained: how does the presence of apoE4 lead to cell damage? Is the presence of apoE4 resulting in a loss of normal apoE3 function, or does the addition of apoE4 cause the toxic effects?

“It’s fundamentally important to address this question because it changes how you treat the problem,” explains Huang, who is also a professor of neurology and pathology at UC San Francisco. “If the damage is caused due to the loss of a protein’s function, you would want to increase protein levels to supplement those functions. But if the accumulation of a protein leads to a toxic function, you want to lower production of the protein to block its detrimental effect.”

To answer this question, the researchers examined brain cells that did not produce either form of the apoE protein, and the neurons looked and functioned just like cells with apoE3. However, if the researchers added apoE4, the cells became riddled with pathologies related to Alzheimer’s disease. This discovery indicates that the presence of apoE4—and not the absence of apoE3—promotes the disease.

Finally, the researchers looked for ways to repair the abnormalities caused by apoE4. In earlier work, Huang and his collaborators developed a class of compounds that can change the structure of the harmful apoE4 protein so it resembles the innocuous apoE3 protein, referred to as apoE4 “structure correctors”.

Treating human apoE4 neurons with a structure corrector eliminated the signs of Alzheimer’s disease, restored normal function to the cells, and improved cell survival. Huang is now working with his collaborators in academia and the pharmaceutical industry to improve the compounds so they can be tested in human patients in the future.

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one gender then two, to many, too many, children and then bodies too. in naming histories a burnt down house in Queens, in reinventing them a dried up beach in Philadelphia. eventually dysphoric blood and Phil Elverum’s glow, but always and ultimately, nada y nada y nada y nada. Side A, tracks 1-10 entitled “FEAR NOT”, is an intimate record about the blood of our genders. Secrets secrets secrets. Side B, tracks 11-20 entitled “OURSELVES ALONE”, is an adventurous record about Phil Elverum. Glow glow glow. These records communicate with each other in the way they understand the histories inscribed on the other, with "FEAR NOT" being an attempt to name histories and "OURSELVES ALONE" being an attempt to reinvent them. Except for my bandmates’ parts tracked in their respective homes, this album was written and recorded with the big heart of DIY at The Closet Mansion in Queens, NY from January 2016-October 2017. Amidst discoveries and mistakes, there is perseverance, experience and endurance.
released February 14, 2018 FEAR NOT OURSELVES ALONE is: Ivan // Ivy - words, vocals, guitar, bass (tracks 1, 2, 5, 7, 10, 11, 12, 13, 14, 16, 19), drums (track 7), synthesizer, production, mixing Jon - guitar, album art Dan - bass (tracks 4, 6, 8, 15, 17, 18, 20), masterting Thank you to Nils for playing drums on tracks 4, 6, 8, 15, 17, 18, 20. Thank you to Sam for playing drums on tracks 1, 2, 5, 10, 11, 12, 13, 14, 16, 19. Thank you to Bryce for singing on track 3. This record is dedicated with all my love to Donald Grim, for introducing me to the blood of our genders and the beaches of Philadelphia. Recommended listenings: “The Glow Pt. 2” by The Microphones: “nobody wouldn’t see good things” by Lemon Meringue Die: Giorgio Brutini Mens Gideon Loafer Black 2jiDOpZf
“divorce lawyers i shaved my head” by jordaan mason and the horse museum: Quiksilver Mens Monkey Wrench Sandals and HDO Travel Sunscreen 15 SPF Spray Bundle Brown / Black / Brown 30DHdc
This record would not exist without the aforementioned works. Mostly, “The Glow Pt. 2” by The Microphones from which much of Side B appropriates its lyrics. In the mode of a found poem, I aimed to make new art from this existing work. All rights to Phil Elverum, his words are not meant to be stolen, but to be used in understanding. “nobody wouldn’t see good things” by Lemon Meringue Die offered inspiration during a period of artistic drought, making beautiful the ways in which intimacy can be achieved through recording and how sampling Phil Elverum’s work can accomplish message. In thinking about the ways in which gender can serve as a means of introspection towards amalgamated histories, I am in debt to the brilliant work of jordaan mason. No art exists in vacuum, no artist in void. thank you // love each other, Ivan // Ivy
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