Understanding Amyloid Plaque Formation and Spread in the Brain

New Method to Track Amyloid Plaques in Alzheimer’s Disease

Understanding Alzheimer’s Disease

Alzheimer’s disease is a neurological condition characterized by impaired memory, cognition, and language, ultimately leading to dementia. The disorder is primarily caused by the accumulation of misfolded proteins that form insoluble aggregates. The two key proteins implicated in the pathogenesis of Alzheimer’s are amyloid-β (Aβ) peptides and tau proteins. These aggregates develop into plaques that can damage neurons, disrupting neural circuits and networks.

Spread of Protein Aggregates

The proteins associated with Alzheimer’s can disseminate through the brain, leading to further aggregation in new cells. This process initiates a chain reaction of protein misfolding and plaque formation. Despite extensive research, there remains a significant gap in understanding the progression of Alzheimer’s disease, particularly concerning the triggers for Aβ deposition and aggregation. Additionally, knowledge about which brain regions are most susceptible to plaque formation is limited, as human tissue samples are typically examined post-mortem, restricting studies to the later stages of the disease. Current methods, such as positron emission tomography (PET) imaging, have struggled to track Aβ amyloid plaque formation, especially in deeper brain structures. Consequently, animal models are often utilized to study disease progression from its onset.

Research Findings on Aβ Aggregate Formation

A recent study from the United States, published in *Communications Biology*, introduced a novel imaging technique to identify when and where Aβ deposits appear in the brains of mice. The researchers utilized genetically engineered 5XFAD mice, which possess mutations that lead to Alzheimer’s disease. Through a technique called SWITCH (System-Wide Control of Interaction Time and Kinetics of Chemicals), the team analyzed the whole brains of the mice at two, four, six, and twelve months of age to monitor disease progression. Their findings revealed that Aβ deposits originate in specific brain regions before spreading to other areas. The most affected regions were identified as the mammillary body, septum, and subiculum, which are core components of the Papez memory circuit.

To confirm that their results were not artifacts of the mouse model, the researchers analyzed both messenger RNA and protein levels throughout the brain. They observed elevated levels of Aβ mRNA across the brain; however, protein plaques formed only in designated areas, thus validating their findings.

Validation in Human Brain Samples

The researchers further validated their results using human brain tissue sections. They hypothesized that if aggregates formed first in the mammillary body, then the quantity of Aβ aggregates would increase in tandem with disease progression. Their analysis of human tissues supported this hypothesis, showing that as Alzheimer’s progressed, the mammillary body became more densely populated with plaques.

Over time, Aβ deposits were found to infiltrate increasingly complex cognitive systems. The plaques initially spread to the default mode network, subsequently advancing to the limbic system, and ultimately encompassing the forebrain—all regions critical to memory and cognition.

Impact of Aβ Aggregates on Neurons

The research team demonstrated that neurons harboring Aβ aggregates exhibited heightened excitability, allowing them to transmit more electrical signals than usual. However, this over-excitability can lead to further Aβ aggregation, exacerbating disease progression. By inhibiting the signaling of these specific neurons, the researchers found that they could prevent the formation of additional aggregates.

This investigation provides essential insights into the origins and spread of amyloid plaques throughout the disease’s course. Understanding how these aggregates contribute to Alzheimer’s symptoms could pave the way for new therapeutic approaches. Dr. Huang, co-lead author of the study, emphasized the importance of identifying circuits and regions exhibiting early neuronal dysfunction, stating that this understanding is critical for developing effective treatments.

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).
Palop, J. J. & Mucke, L. Amyloid-β–induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nature Neuroscience 13, 812 (2010).
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 (2019).
Image by Raman Oza from Pixabay.