American Scientist

The neurons from this particular type of mouse looked perfectly normal, which surprised neuroscientist Erik Bloss and his colleagues because the nerve cells were surrounded by foreboding clumps of proteins. They could see the fingerlike, highly branched protrusions that extend from the nerve cell’s body, called dendrites, that are the receiving end of neuronal communication. Along these protrusions are even smaller structures, called dendritic spines, where synapses form and pass impulses between neurons. The classic inbred laboratory mice that researchers typically use to model human diseases show dramatic changes in these structures when their brains accumulate anomalous protein clumps, much like in human brains that develop dementia. However, the strain this group was studying—derived from mice caught more recently in the wild—seemed unperturbed.

In a study published in the journal Alzheimer’s & Dementia, Bloss and geneticist Gareth Howell at the Jackson Laboratory in Maine, as well as Sarah Heuer, now a postdoctoral research associate in genetics at Brigham and Women’s Hospital in Boston, examined specific differences in neuronal circuitry, as well as changes at the single neuron level, that may explain the wild-derived mice’s resilience to pathological proteins. Howell, whose research focuses on Alzheimer’s disease, explained that a hallmark of this illness is the accumulation of toxic clumps of what are called amyloid beta peptides, which ultimately lead to brain cell death. In human populations, Alzheimer’s is a highly complex and genetically diverse disease. Yet most studies in mouse models focus on one genetic strain, B6, which has been purposely inbred for research since 1921 and housed in a laboratory setting since 1951, dramatically decreasing their genetic diversity. Although this genetic limitation is useful for some research because it allows scientists to specifically disrupt a single gene and minimize variability across laboratories, sometimes it is detrimental to new research discoveries.

Howell’s goal has long been to better incorporate genetic diversity in the study of Alzheimer’s disease. He and his colleague, neuroscientist Kristen Onos, have access to mice with diverse backgrounds, so they first investigated what happened when they introduced human proteins into the brains of a few wild-derived strains of mice, which usually causes a buildup of amyloid plaques. In the commonly used B6 strain, this toxic amyloid accumulation would cause neuronal loss and cognitive decline with age, similar to Alzheimer’s. However, the wild-derived mouse strain, called PWK, appeared cognitively normal, healthy, and resilient.

To zoom in on this cognitive resilience, the researchers investigated a specific neuronal circuit known to play a role in the progression of Alzheimer’s, which may be altered by microglia, essential cells in the nervous system that help neurons fight injury and maintain their synaptic health. Their activity goes awry in various diseases, including Alzheimer’s. Using high-resolution microscopy, the researchers measured the diameter of dendritic spine heads (see figure below), which correlates to synaptic strength, as well as the density of synapses on a given dendrite. They found a microglia-dependent increase in spine density in B6 mice that model Alzheimer’s, but not in B6 mice that undergo normal aging. Bloss thought this result suggested that Alzheimer’s triggers a “biphasic response, where neurons are first hyperexcitable, and then they lose activity and start to degenerate.”

In contrast, PWK mice modeling Alzheimer’s were highly resilient to spine changes, even when only analyzing dendritic spines directly touching microglia. Even at this micro-scale level, PWK mice did not respond to amyloid plaque accumulation. Recently, Heuer also showed that PWK mice neurons have less age-induced synapse loss, suggesting that genetic differences make these neurons strong even in a healthy state. She was surprised to see that the team’s original hypothesis—that PWK mice are resilient to dendritic spine changes—turned out to be true: “It’s not very often when your first hypothesis is actually supported in science.” 

The team hopes to sequence the two strains across multiple stages of life in order to identify gene–protein signatures that promote this resilience in PWK mice. They also plan to investigate other neuronal circuits to see if diverse neuronal populations follow the same pattern. Bloss remarked, “It's among the first steps towards finding the mechanisms of resilience, which we hope can be harnessed for more personalized treatments in high-risk individuals to prevent, or at least delay, disease.”