Cognition and behavior rely on communication between individual neurons and extensive interactions between neural networks. But when synaptic dysfunction occurs, the results can be dire, leading to neurodegenerative symptoms in Alzheimer’s disease.
“The brain is the seed of our personal identity,” said Valina Dawson, Ph.D., director of neurogeneration and stem cell programs at Johns Hopkins University in Baltimore, Maryland. “It allows us to interact with our world but when things go wrong in the brain, it’s disastrous for the individual as well as the family.
“Our ability to treat these diseases is limited at the moment. We need new insight into what goes wrong.”
A lesser-known protein
Researchers, for years, have targeted amyloid beta (Aβ) in attempts to halt the progression of Alzheimer’s disease, and have recently, shown increased interest in the protein, tau.
Read More: Toxic Tau Could be Key to Alzheimer’s Treatment
But Paula Pousinha, Ph.D., at the French National Centre for Scientific Research, has focused her research on a lesser-known protein fragment: amyloid precursor protein intracellular domain (AICD). AICD is a fragment of amyloid precursor protein (APP), which is formed at the same time as Aβ in the brain. New evidence suggests that in addition to Aβ, AICD also disrupts communication between neurons during the progression of Alzheimer’s disease. Pousinha presented these published findings at this year’s Society for Neuroscience (SfN) conference, which took place from October 17 to 21 in Chicago.
“Although AICD has been known for more than 10 years, it has been poorly studied,” said Pousinha.
Pousinha’s research team demonstrated that overexpressing AICD levels with AAV vector in rats’ brains “perturbs neuronal communication in the hippocampus,” a key structure necessary in forming memories and an area earliest affected in Alzheimer’s disease.
“In normal animals, if we apply to these neurons a high-frequency stimulation, afterward the neurons are stronger,” said Pousinha. “Neurons where we overexpressed AICD failed to have this potentization.”
Pousinha doesn’t negate the importance of Aβ in the development of neurodegenerative diseases. “Our study doesn’t exclude the pathological effects of Aβ,” she said. “We believe that Alzheimer’s disease is much more complex and has more than one candidate that has implications.
“It’s very important for the scientific community to understand the role of all these APP fragments of neuroinflammation — different pieces of the puzzle of how we can stop the disease progression.”
How do memories persist in the brain long term?
New research, also presented at this year’s SfN, has implications for understanding memory to develop treatments for Alzheimer’s disease and dementias. Sakina Palida, a graduate student at the University of California, San Diego found that localized modifications in the perineuronal net (PNN) at synapses could be a mechanism by which information is stably encoded and preserved in the brain over time.
“We still don’t understand how we stably encode and store memories in our brains for up to our entire lifetimes,” said Palida. The prevailing idea on how memories are maintained over time generally focuses on postsynaptic proteins, said Palida. “But the problem with looking at intracellular synaptic proteins is that the majority turn over rapidly, of hours to at most a few days. So they’re very unstable.”
So, Palida and her team identified PNN as an ideal substrate for long-term memory. “Kind of like how you carve into stone — stone is a stable substrate — you retain the information regardless of what comes and goes over it.” They demonstrated that individual PNN proteins are highly stable, and that the PNN is locally degraded when synapses are strengthened.
And the team also demonstrated that mice lacking enzymes that degrade the PNN have deficient long-term, but not short-term, memory. “Which is a really exciting new result,” said Palida.
To track the PNN in live animals, Palida and her team fused a fluorescent protein to a small link protein in the PNN to allow tracking of PNN dynamics in real time. They also monitored PNN degradation in live cells after stimulating neurons with brain-derived neurotrophic factor (BDNF), a chemical secreted in the nervous system to enhance signaling — and observed localized degradation of the PNN at some newly formed synapses.
What’s next? “We’re currently making transgenic animals to express this protein, which would allow us to monitor PNN dynamics simultaneously with synaptic dynamics in a live animal brain, and really investigate this hypothesis further,” said Palida.
Filed Under: Drug Discovery
