In recent debate over the FDA’s approval of the Alzheimer’s drug aducanumab, we’ve heard a lot about the “amyloid hypothesis.” In that context, it’s refreshing to learn about a model of Alzheimer’s neurodegeneration that doesn’t start with the pathogenic proteins amyloid or Tau.
Instead, a new paper in Alzheimer’s & Dementia from Emory neuroscientist Shan Ping Yu and colleagues focuses on an unusual member of the family of NMDA receptors, signaling molecules that are critical for learning and memory. Their findings contain leads for additional research on Alzheimer’s, including drugs that are already FDA-approved that could be used preventively, and genes to look at for risk factors.
“It’s not just another rodent model of Alzheimer’s,” Yu says. “We are emphasizing a different set of mechanisms leading to neurodegeneration.”
Tap tap tap ka-CHUNK! That was the sound of fruit flies being given concussions in an Emory laboratory recently.
Emory MD/PhD student Joe Behnke, working with neuroscientist James Zheng, has developed a model for studying repetitive head trauma in the fruit fly Drosophila melanogaster – analogous to CTE (chronic traumatic encephalopathy) in humans. The results were published in Scientific Reports.
CTE is a term for neurodegeneration linked to repeated concussions or blows to the head, which has been observed in athletes and military veterans. Head trauma has also been linked to other neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS (amyotrophic lateral sclerosis).
What’s critical about using fruit flies is that it speeds up time. It can take years or decades for CTE or other neurodegenerative conditions to appear in humans, but Behnke and Zheng can experiment with a mutant fly strain or other interventions in a few weeks. They describe their model as a platform for future studies, in which they can unleash all of the genetic tools fruit flies have to offer.
To begin with, Behnke worked out a system for giving flies controlled blows to the head. He says that it exploits the climbing instinct flies have when startled, called negative geotaxis. When he taps a vial with flies in it three times, they reorient themselves and begin climbing up. Then a stronger blow, delivered in a crash test-like apparatus, gives flies the desired head injury. Previous models in flies hadn’t really focused on the head, but gave them injuries all over their bodies.
Already, Behnke and Zheng have been able to demonstrate that female fruit flies are more vulnerable to repeated head injuries than males. Repeated head injury results in locomotor deficits and shortened lifespan and accelerates age-related degeneration.
An influential theory about the anatomical trajectory of Parkinson’s disease is getting a microbial boost. The idea, first proposed by neuroanatomist Heiko Braak in 2003, is that pathology and neurodegeneration start in the intestines and then travel to the brain. See this article in Scientific Americanfor background.
Illustration showing neurons with Lewy bodies, depicted as small red spheres, which are deposits of aggregated proteins in brain cells
Timothy Sampson, in Emory’s Department of Physiology, was first author on a recent paper in eLife, which explores the idea that prion-like proteins produced by intestinal bacteria can accelerate the aggregation of similar proteins found in our cells. The findings suggest that interventions targeting intestinal bacteria could modulate neurodegeneration.
Sampson, a former Emory graduate student who did postdoctoral work in Sarkis Mazmaniam’s lab at Caltech, says he will continue the project here. He and his colleagues were looking at the interaction between a bacterial protein called Curli – involved in adhesion + biofilms — and the aggregation-prone mammalian protein alpha-synuclein, known as a main component of the Lewy body clumps seen in Parkinson’s. The experiments were in a mouse model of Parkinson’s neurodegeneration, in which human alpha-synuclein is overproduced.
Looking ahead, Sampson says he is interested in what signals from the microbiome may trigger, accelerate or slow synuclein aggregation. He’s also looking at where in the GI tract synuclein begins to aggregate, possibly facilitated by particular cells in the intestine, and whether the observations with alpha-synuclein hold true for other proteins such as amyloid-beta in Alzheimer’s.