Summary: A new study provides novel insights into the molecular basis of Alzheimer’s.
Source: Northeastern University.
New research led by Northeastern University suggests that Alzheimer’s disease may not progress like falling dominoes, as conventional wisdom holds, with one molecular event sparking the formation of plaques throughout the brain. Instead, it may progress like a fireworks display, with a unique flare launching each plaque, one by one.
The study, headed by Lee Makowski, professor and chair of the Department of Bioengineering, was published Thursday in the journal Scientific Reports.
“I believe the findings will provide us with a new way of thinking about the molecular basis for Alzheimer’s disease progression,” says Makowski. “Once you do that, you can start asking the right questions about how to prevent it.”
More than 5 million Americans are living with Alzheimer’s disease, according to the Alzheimer’s Association. It is the sixth leading cause of death in the U.S., the association reports, killing more people than breast and prostate cancers combined.
Yet much about its cause and the mechanisms driving its progression remain unknown. Alzheimer’s disease typically starts with the death of brain cells, or “neurons,” in one part of the brain and then, over time, slowly spreads to other regions. Amyloid fibrils—thin rigid strands of protein aggregates—accumulate in these areas of neuronal death, packing together to form dense plaques.
“Just as there are different strains of a virus, there appear to be different strains of fibrils,” explains Makowski. “Remarkably, the different strains have the same chemical makeup but different three-dimensional structures.”
Insight into therapies
It was the structures that Makowski’s team zeroed in on.
In collaboration with researchers from Massachusetts General Hospital and Argonne National Laboratory’s Advanced Photon Source, Makowski and former research associate Jiliang Liu, PhD’15, scanned slices of brain tissue retrieved at autopsy from four people with Alzheimer’s and one with no history of dementia using an X-ray beam just five microns across. They then built images of the fibrous structures within the plaques from the thousands of diffraction patterns they collected.
Because fibrils self-propagate, researchers have speculated that all fibrils in a given brain are of the same strain and hence have the same structure. That led to the assumption that a single molecular event initiated their accumulation into plaques and the subsequent cascading progression of the disease.
“Our data wasn’t consistent with that,” says Makowski. “We found that fibrils with distinctly different structures can accumulate in the same brain, even in plaques quite close to one another. This strongly suggests that there is not one event that initiates fibril formation throughout the brain but many. Our research indicates that it is the condition under which fibrils form that slowly propagates through the brain and triggers a distinct initiation event for each plaque.”
Think of a cold front traveling south from Massachusetts to Virginia. It’s raining up and down the East Coast. When conditions are right in Massachusetts—that is, when the temperature drops to 32 degrees—the rain turns to snow (the initiation event). Virginia, however, doesn’t get any snow until a week later when its temperature drops to the freezing point. As in the brain, the conditions drive the event.
“The findings are important because they change the way we think about disease progression,” says Makowski. “It gives us a new point of view from which to develop hypotheses about the conditions that lead to the formation of fibrils and plaques.”
The researchers also showed that the structure of the fibrils may vary based on a person’s clinical history. For example, the fibrils of one woman who had exhibited no signs of dementia prior to death were distinctly different from those found in the others, who had Alzheimer’s disease.
“This may mean that some strains of fibrils are associated with disease whereas others are not,” says Makowski. “Distinguishing between them may provide critical insights for developing therapies to slow, halt, or reverse the neurodegeneration associated with Alzheimer’s disease.”
Source: Mehdi Moussaïd – Northeastern University
Image Source: NeuroscienceNews.com image is adapted from the Northeastern press release.
Original Research: Full open access research for “Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue” by Jiliang Liu, Isabel Costantino, Nagarajan Venugopalan, Robert F. Fischetti, Bradley T. Hyman, Matthew P. Frosch, Teresa Gomez-Isla and Lee Makowski in Scientific Reports. Published online September 15 2016 doi:10.1038/srep33079
[cbtabs][cbtab title=”MLA”]Northeastern University “Study Offers ‘Critical Insights’ for Treating and Preventing Alzheimer’s.” NeuroscienceNews. NeuroscienceNews, 14 September 2016.
<https://neurosciencenews.com/alzheimers-treatment-prevention-5059/>.[/cbtab][cbtab title=”APA”]Northeastern University (2016, September 14). Study Offers ‘Critical Insights’ for Treating and Preventing Alzheimer’s. NeuroscienceNew. Retrieved September 14, 2016 from https://neurosciencenews.com/alzheimers-treatment-prevention-5059/[/cbtab][cbtab title=”Chicago”]Northeastern University “Study Offers ‘Critical Insights’ for Treating and Preventing Alzheimer’s.” https://neurosciencenews.com/alzheimers-treatment-prevention-5059/ (accessed September 14, 2016).[/cbtab][/cbtabs]
Abstract
Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue
Aggregation of Aβ amyloid fibrils into plaques in the brain is a universal hallmark of Alzheimer’s Disease (AD), but whether plaques in different individuals are equivalent is unknown. One possibility is that amyloid fibrils exhibit different structures and different structures may contribute differentially to disease, either within an individual brain or between individuals. However, the occurrence and distribution of structural polymorphisms of amyloid in human brain is poorly documented. Here we use X-ray microdiffraction of histological sections of human tissue to map the abundance, orientation and structural heterogeneities of amyloid. Our observations indicate that (i) tissue derived from subjects with different clinical histories may contain different ensembles of fibrillar structures; (ii) plaques harboring distinct amyloid structures can coexist within a single tissue section and (iii) within individual plaques there is a gradient of fibrillar structure from core to margins. These observations have immediate implications for existing theories on the inception and progression of AD.
“Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue” by Jiliang Liu, Isabel Costantino, Nagarajan Venugopalan, Robert F. Fischetti, Bradley T. Hyman, Matthew P. Frosch, Teresa Gomez-Isla and Lee Makowski in Scientific Reports. Published online September 15 2016 doi:10.1038/srep33079
