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AAV Vector carrying APOE2 Allele​ ​Reduces Amyloid Buildup in the Brains of Alzheimer’s Mice

Adeno, Adeno-Associated​ ​Virus

 

Which one of these is not like the others: heart disease, cancer, chronic lower respiratory diseases, accidents, stroke, Alzheimer’s disease, diabetes, influenza/pneumonia, nephritis, and suicide. All of these ailments are catalogued by the CDC as “leading causes of death,” yet Alzheimer’s is the only fatal disease among them that currently cannot be “prevented, cured or even slowed.” [1][2] 

The frontier of scientific research is therefore consumed with cracking the tough nut that is the rapid deterioration of an Alzheimer’s addled brain. Breakthroughs leapfrog over one another as progress slogs forward.

In a April 2016 study, science increased its forward momentum by dragging genetic manipulation into the fight, introducing a revolutionary way to approach any looming disease.

APOE4: A Potential Doom Marker

Biology 101 teaches that an individual inherits two copies of a given gene, one copy from each parent. Genes come in assorted varieties; sometimes there are fewer versions, or alleles, and sometimes there are many more. APOE4 is one of three possible alleles for the APOE gene which codes for bodily apolipoprotein, a protein which helps construct the lipid-conveying lipoprotein. Yet not all alleles are created equal. Inheritance of the APOE4 genetic marker, whether heterozygous or homozygous, is linked to increased likelihood of developing Alzheimer’s disease later in life, as well as earlier symptomatic onset.

Most members of the populace possess APOE3, a form which seems to bear no relation to Alzheimer’s risk altogether. One of the gene’s other allelic counterparts, APOE2, actually reduces Alzheimer’s risk by approximately 50 percent- or at least delays first symptoms until an advanced age of onset, depending on the case in question. Years ago, an individual’s genetic fate was etched permanently in stone as his allotment of alleles was nontransferable. Simply put- you get what you get and you don’t get upset. Modern research, however, dares to reach directly into the human genome and alter the instruction pattern, thereby changing genetic predisposition for disease.

Game-Changing Brain Changer

First, it is important to understand the nature of the influence that the APOE gene yields over Alzheimer’s. While the exact mechanism of its impact remains murky, APOE seems to be related to the level of beta-amyloid buildup in the brain. Excessive beta-amyloid formation presents as ungainly plaques, largely responsible for Alzheimer’s steep cognitive decline. Experimenters therefore formulated a hypothesis; the APOE4 allele may somehow encourage unusual brain beta-amyloid synthesis while the APOE2 allele may inhibit those same clumpy configurations. Perhaps forcibly integrating the APOE2 allele into the genome of an APOE4-stricken individual could prevent or even reverse beta-amyloid’s inexorable accumulation, issuing a mighty blow against Alzheimer’s regime.

Viruses Can Be Helpful Too

How can scientists introduce a particular gene into a foreign genome? They actually hijack a relatively harmless virus called an adeno-associated virus, strip it of its viral DNA, and infuse it with DNA of their own design. Since viruses typically conquer the body by injecting their DNA into unwitting host cells and forcing proliferation, such modified viral carriers can insinuate choice genes into the cell’s pre-existing genetic fabric. These viruses are conveniently recombinant so they readily incorporate new DNA segments for therapeutic purposes.

Researchers prepared a fleet of adeno-associated virus vectors carrying the APOE2 allele and injected them intrathalamically into the brains of anesthetized mice. First, the researchers aimed to evaluate whether the newly introduced human APOE2 would undertake its regular function. They therefore, began with pre-bred knockout mice (EKO) which lacked any version of the APOE gene altogether, observing initial results. Simultaneously, they designated a group of mice as targeted replacement mice, a population which would receive the APOE2 addition on top of the innate APOE gene. Neither of these preliminary setups would directly address the beta-amyloid question, but would establish the baseline properties of APOE2 delivery. Only afterward did the experimenters engineer a mouse population with an over-expressive amyloid precursor protein (APP) gene to amp up brain beta-amyloid burdens to Alzheimer’s-equivalent levels. The mouse Alzheimer’s models then received APOE2 injections as the project’s critical stage unfolded.

The Results Are In

Delivery was a success. APOE knockout mice and targeted replacement mice without the amyloid precursor protein mutation largely exhibited normal apolipoprotein function once the APOE2 gene was instituted. That small victory, however, did not guarantee that the APOE2 introduction could combat the monstrous beta-amylid buildup in simulated Alzheimer’s mouse brains. Yet the results withstood further investigation. APOE2-treated mouse brains boasted significantly reduced beta-amyloid presence; the plaque presence was evaluated both before and after treatment via selective chemical staining, and the diseased surface area did recede after APOE2 exposure.

Could the uplifting report owe its thanks to neurotoxicity? Scientists feared that overexpression of APOE could potentially have had a poisonous effect on surrounding tissue, killing off neurons and distorting readings. Degeneration-specific neuron staining soon alleviated these concerns, as screenings returned only negative results.

Would the promising effects remain consistent in targeted replacement mice which already contained the troublemaking human APOE4 gene? True, APOE2 had the capacity to somewhat resolve plaque buildup- but could it directly combat an antagonistic APOE4 gene working in the opposite direction? The answer proved to be a tentative but optimistic yes. APOE2 demonstrated a “protective effect,” coaxing beta-amyloid into relative submission. While it certainly did not wipe the slate clean, the increased APOE2 level did elicit a notable decline in beta-amyloid deposits. When APOE2 and APOE4 are present in tandem, it appears that APOE2 can still grapple for the upper hand. [3]

What Now?

Sadly, no new Alzheimer’s drug is apt to hit the market just yet. The APOE4 gene is only an Alzheimer’s risk factor- not a deterministic guarantee. Many cases bear no relation to APOE whatsoever, and some people with the APOE4 allele never develop the disease at all. Nevertheless, APOE4 may account for up to a quarter of all Alzheimer’s instances. As the field of genetics becomes increasingly comprehensive, further genomic ties may be uncovered. This viral gene therapy

As the field of genetics becomes increasingly comprehensive, further genomic ties may be uncovered. This viral gene therapy is therefore, a new weapon in the battle against Alzheimer’s, and perhaps one step closer to an eventual cure.

Sources:

[1] http://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm
[2] http://www.alz.org/facts/
[3] http://www.ncbi.nlm.nih.gov/pubmed/27318144
[4] http://www.alz.org/research/science/alzheimers_disease_causes.asp

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    By: Avigail Goldberger

    Avigail Goldberger is an avid science devotee, with a particular interest in biology, genetics, and neuroscience. Her love of STEM subjects is equally matched by a passion for literature and writing, so she hopes that her eventual profession will synthesize her multifaceted academic drives.

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