Researchers develop a new way to track where amyloid plaques start in the brain, and where they spread in Alzheimer’s.
Alzheimer’s disease is a neurological disorder that is characterized by impaired memory, cognition, language, and eventually results in dementia. The disease is caused by the accumulation of misfolded proteins that form insoluble aggregates. The two main proteins that are involved in the pathogenesis of Alzheimer’s are amyloid-β (Aβ) peptides and tau proteins. These aggregates eventually form plaques that can cause degradation to neurons, disrupting neural circuits and networks.
Proteins aggregates spread through the brain
These proteins can spread through the brain and cause further aggregation in new cells resulting in a chain reaction of protein misfolding and plaque development. There is a gap in our understanding of how Alzheimer’s disease progresses and not much is known about what triggers Aβ deposition, aggregation, and progression. Not much is known about which parts of the brain are vulnerable to plaque formation, and our understanding of where the first Aβ deposits form in the brain is limited. This is difficult to research in humans because human tissue samples are only analyzed post mortem, meaning that we can only study the last stages of disease progression. Attempts to track Aβ amyloid plaque formation in humans using positron emission tomography (PET) imaging has been challenging and imaging of deep structural regions of the brain has not been attempted. This means that animal models provide the best option for researching disease progression from the beginning of disease onset.
Researchers investigate where Aβ aggregates start and how they spread
In a recent US study published in Communications Biology, researchers used a new imaging technique to track when and where Aβ deposits occurred in the brains of mice. The scientists used genetically engineered mice (5XFAD mice) that have mutations that cause Alzheimer’s disease. They used a new imaging technique called SWITCH (System-Wide Control of Interaction Time and kinetics of Chemicals) to analyze the brains of mice. The researchers looked at whole-brains when the mice were two, four, six, and twelve months old to track disease progression. They were able to show that Aβ deposits start in specific regions of the brain and then spread to different parts of the brain. The regions in the brain that were most susceptible to aggregate development were the mammillary body, septum, and subiculum- core regions of the Papez memory circuit. The scientists made sure this wasn’t an artefact of their mouse model by looking at both messenger RNA and protein levels throughout the brain. They noticed high levels of Aβ mRNA throughout the brain but the protein plaques only formed in specific regions of the brain, validating their findings and showing that their results were not caused by the animal model they used.
Human samples have a similar pattern of Aβ deposition
Importantly the scientist validated their findings in human brain sections. They speculated that if the aggregates form in the mammillary body first, then the amount of Aβ aggregates should increase proportionally with the stage of disease progression. When the team looked at human tissues this was what they found, the later the stage of Alzheimer’s the more densely packed the mammillary body was with plaques.
Over time, Aβ deposits were forming in increasingly complex cognitive systems. The plaques spread to default-mode network, and then moved into the limbic system. Finally, the plaques arose throughout the forebrain. These structures are all involved in memory and cognition.
Aβ aggregates excite neurons
The team then went on to show that the cells that had Aβ aggregates were more excitable, meaning these neurons were able to carry more electronic signals than normal. The researchers showed that the brain cells that were located in subcortical regions of the brain were dysfunctional due to high levels of Aβ aggregates. This is problematic because when neurons are over-excitable they can cause the cells to create more Aβ aggregates, contributing to disease progression. The scientist then prevented the signaling of these specific neurons and found that preventing the signaling prevented the formation of aggregates.
This investigation gives important insights into where amyloid plaques start and how they spread over the course of the disease. This will help researchers understand how these aggregates contribute to the symptoms seen in Alzheimer’s, which in turn may lead to the development of novel therapies in the future. Dr. Huang co-lead author on this investigation, stated in a press release, “At that point, it would be hard to cure the symptoms. It’s really critical to understand what circuits and regions show neuronal dysfunction early in the disease. This will, in turn, facilitate the development of effective therapeutics.”
Written by Tarryn Bourhill MSc, PhD Candidate.
References:
- Brettschneider, J., Del Tredici, K., Lee, V. M.-Y. & Trojanowski, J. Q. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nature Reviews Neuroscience 16, 109 (2015).
- Musiek, E. S. & Holtzman, D. M. Three dimensions of the amyloid hypothesis: time, space and’wingmen’. Nature neuroscience 18, 800 (2015).
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Palop, J. J. & Mucke, L. Amyloid-β–induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nature neuroscience 13, 812 (2010).
4.Canter, R. G. et al. 3D Mapping Reveals Network-specific Amyloid Progression and Subcortical Susceptibility. bioRxiv, 116244 (2017).
- Orenstein, D. Study pinpoints Alzheimer’s plaque emergence early and deep in the brain, <https://www.eurekalert.org/pub_releases/2019-10/piam-spa100319.php> (2019).
Image by Raman Oza from Pixabay
