BAR HARBOR — Mike Sasner is a soccer fan, so he describes his excitement about recent progress in Alzheimer’s research this way: “We’re taking better shots on goal, and we’re also taking more shots on goal.”
The goal in this analogy, the longtime Jackson Laboratory research scientist said, is identifying ways to detect the disease earlier and create treatments that will slow or stop its progression.
Researchers are taking “better shots” because their understanding of the disease mechanisms is much more sophisticated. This includes specific gene sequences and gene expression patterns believed to correlate with higher risk of developing the disease.
Research groups at The Jackson Laboratory and colleagues from other institutions in a new Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD) Center are creating mouse models, strains of mice genetically manipulated to model human disease.
Then when there are potential therapies ready to test, preclinical studies of those therapies with these mice will hopefully be more predictive of how the therapies will work on humans.
They’re taking “more shots” because, using gene editing techniques, they can create many more of these models. The new mouse models are also more diverse and more representative of natural genetic variation, including mouse strains from all over the world. That’s important because disease progresses differently in different mice, as it does in different people. Some are “resilient,” or resistant, with respect to a disease, and some have higher risk. And different mice respond differently to therapies.
There is no cure for Alzheimer’s disease, and it’s a growing problem. Deaths attributed to Alzheimer’s increased 145 percent between 2000 and 2017, according to the National Center for Health Statistics. The disease represents a huge expense for families, many of whom provide unpaid care, and for public programs such as Medicare.
Mice are a particularly good tool for studying Alzheimer’s for a whole host of reasons.
Human biology and mouse biology are very similar; more than 95 percent of our genes are the same.
“We get the same diseases” as mice, Professor Ken Paigen said at a recent Jackson Laboratory event. “We get them for the same reasons, and very much the same genes are involved.”
Also, Sasner said, you can’t study neurodegenerative disease in a dish or a test tube.
“You need a brain to study a brain,” he said.
Mice only live two to three years. A mouse that’s 18 to 24 months old shows signs of aging comparable to those seen in humans 56 to 69 years old. Researchers can collect data on the biology of the mice beginning earlier in life, to track the disease progression long before any loss of neurons or symptoms of cognitive decline are apparent.
“It used to be, we’d make an animal model of Alzheimer’s disease and we’d see if the mouse could run in a maze,” Sasner said. “And if we give them a drug and they run the maze better, well, we’ve cured Alzheimer’s.”
But none of those drugs have panned out. There have been hundreds of clinical trials of drugs for Alzheimer’s and essentially all have failed.
So now the thinking is, what the mice does (behavioral assays, in research parlance) is not a good enough indicator of what’s happening in its brain.
Maybe the mice ran the maze better just because they’re running faster, he said. “Maybe they’re more motivated. There’s all kinds of complicating factors why behavioral assays in mice [may not] correlate to humans.”
Symptoms of cognitive decline only show up when Alzheimer’s is far progressed. That happens when significant numbers of neurons atrophy and stop working. The cerebral cortex shrivels up and the hippocampus, which is needed for forming new memories, shrinks.
Neurons are the only kind of brain cells most people know about. But supporting cells called microglia are now central to Alzheimer’s research.
“We’ve always thought neurons do the work and these other cells just support them and physically provide glucose, etc.” Sasner said. “Now we’re learning that they’re actually playing a very important role.”
During brain development, microglia help create and strengthen neural connections. They also tear away connections that aren’t needed.
“We’re seeing that those same processes happen in disease. Instead of getting rid of the synapses that are not functioning, the microglia are overactive, getting rid of synapses that are functioning.”
A protein called amyloid sometimes congeals to become amyloid plaque. In a healthy brain, “the microglia take out the trash so [the plaque] doesn’t accumulate,” Sasner said.
However, buildup of plaque alone does not necessarily mean you have or will get Alzheimer’s. “If you look at everyone who died at age 80, a lot of people have amyloid [plaque] in their brains,” he said, “and a lot of those people have no cognitive deficits at all.”
Buildup of amyloid plaques and another kind problematic protein aggregation called tau tangles, along with microglial inflammation, are believed to be the problems that lead to damage and death of neurons in Alzheimer’s.
It’s possible with medical imaging technology to look inside a human brain while the person is alive to look for buildup of plaques and tangles. It requires an MRI or PET scan with a specific radioactive nucleotide to label the amyloid, Sasner said.
“We label a nucleotide, we attach it to something that sticks to amyloid, we inject it into the person, and then we can see how much amyloid that person has.”
It’s possible, but it’s extremely expensive and complicated. And the patient “has to be within an hour of Boston,” he said, “because the radionucleotides are made in Boston and they decay in a half-life of hours.”
Otherwise, images of human brains with Alzheimer’s mostly come from postmortem study.
So “in humans, we’re always looking at snapshots,” Sasner said, which leaves a lot of gaps in the data.
Mouse models are helping researchers address many of those gaps. Researchers are focusing on what’s going on in the mice, especially gene expression — the appearance of a particular characteristic attributed to a gene. And they’re comparing that to data from Alzheimer’s patients, collected by colleagues at hospitals.
“We can isolate microglia, sequence gene expression in the microglia, separate from the neurons, so we really have accurate ways of studying these things now,” Sasner said.
“If [researchers] give a drug to a mouse and this set of genes that are expressed in neuro-inflammatory pathways go down, and that’s what we see in humans with Alzheimer’s and not in humans who are normal,” that’s a much better indicator that the drug may be worth continuing to work on, he said.
The MODEL-AD mouse models include mice whose genes have been altered in one of three ways: knockout models, in which genetic material has been removed; transgenic models, in which material has been added to gain function; and humanization, in which human genes have been added in the corresponding locus in the mouse DNA.
“Most disease isn’t caused by a knock-out, it’s caused by a specific over-expression or under-expression of a gene,” Sasner explained, “or a mutation of a gene.”
So those genes are the focus of most of the new models.
Some of the “knocked-in” genetic material is there to help with imaging — ways to get information about the mouse brains without needing the PET scan used for humans.
Sasner and his team added genetic material for a green fluorescent protein (GFP) — the kind that makes fireflies light up — to some of the models.
“Everywhere a microglia is, that microglia will express GFP,” he said.
That is helping them see, using only a microscope, “how the microglia are increasing in number, decreasing in number, migrating toward amyloid, whatever they’re doing.”
They’re also taking huge amounts of health data from the mice on an ongoing basis, studying the characteristics of the mouse just as you’d study the characteristics of a patient.
They’re comparing that data with data from human patients in hopes of improving early diagnosis and developing treatments.
There’s a long way to go, but the team’s attention is firmly fixed on that goal at the end of the field.