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Medical News Today
Study challenges current views about toxic plaque formation in Alzheimer's
By Paul Ian Cross, PhD,
13 hours ago
Recent research uncovers new mechanisms for plaque formation in Alzheimer’s disease. Design by MNT ; Photography by Richard Bailey/Getty Images & The Journal of Cell Biology, CC BY-NC-SA 2.0. This article originally appeared on Medical News Today
New research shows that glial cells play an important role in producing amyloid beta, a protein linked to Alzheimer’s disease.
The study, undertaken by scientists at the Max Planck Institute, challenges long-standing views and could lead to new treatment approaches for the disease.
Although Alzheimer’s disease remains incurable, these findings may help to develop therapies aimed at delaying plaque formation and slowing disease progression at an early stage.
Alzheimer’s disease , which is the most common form of dementia , affects millions of individuals globally, and cases are reportedly on the rise.
Beta-amyloid , a naturally occurring brain protein, is key to the disease’s progression as it builds up in insoluble clusters, forming plaques between neurons and causing damage.
Now, scientists at the Max Planck Institute (MPI) for Multidisciplinary Sciences have discovered that, along with neurons, certain glial cells in the brain also produce amyloid beta.
Their new research, published in Nature Neuroscience , challenges the previously accepted notion that neurons were the only source.
Are new therapeutic strategies for Alzheimer’s on the horizon?
While Alzheimer’s disease currently has no cure, some treatments aim to reduce amyloid plaques in the brain, potentially slowing the disease’s progression.
Previously, neurons were believed to be the primary source of amyloid beta and the main focus for drug development.
First author Andrew Octavian Sasmita, PhD , currently a postdoctoral researcher in the Department of Anatomy and Neuroscience at University College Cork in Ireland, explained the key findings of this new study to Medical News Today .
“Although neurons are thought to be the sole producers of beta-amyloid which gets deposited into extracellular plaques — one of the primary pathologies in Alzheimer’s disease — the myelinating glia of the central nervous system, oligodendrocytes, also produce beta-amyloid and contribute to plaque deposition,” he told us.
“We also observed that excitatory neurons in the cortex and the hippocampus are essential for plaque deposition in deeper brain layers, hinting at a plaque seeding effect over long distances via neuronal projections,” Sasmita added.
“By combining findings from different arms of our study, we observed that a certain threshold concentration of beta-amyloid is essential for major plaque deposition, which is an often overlooked concept in Alzheimer’s disease research.”
– Andrew Octavian Sasmita, PhD
BACE1 inhibition uncovers key role in amyloid plaque formation
Nervous system cells generate amyloid beta by cutting a larger precursor molecule with the aid of an enzyme called BACE1.
In their experiments, researchers selectively disabled BACE1 in the neurons and oligodendrocytes of mice.
They then employed 3D light-sheet microscopy to examine plaque formation across the entire brain, offering a comprehensive view of amyloid plaques in all brain regions.
Oligodendrocytes without BACE1 showed approximately a 30 percent reduction in plaque formation, while removing the BACE1 gene in neurons led to over a 95 percent decrease in plaques.
The researchers also discovered that plaques only form when a specific level of amyloid beta from neurons is present, at which point oligodendrocytes contribute to plaque build-up.
According to the scientists, if BACE1 is effectively inhibited before reaching this threshold, plaque formation could be delayed, potentially slowing the early progression of Alzheimer’s disease.
“Previously, attempts to silence beta-amyloid production via beta secretase (BACE) inhibition in clinical trials were met with unwanted effects, including worsening cognitive functions and shrinkage of brain regions including the hippocampus, which is crucial for memory. This is mostly due to off-target effects of silencing BACE, which is crucial for neuronal well-being.”
– Andrew Octavian Sasmita, PhD
Sasmita added that “silencing oligodendroglial BACE and beta-amyloid production could serve as an alternative target for beta-amyloid reduction.”
“We hope that our data aids in the development of anti-beta-amyloid therapies, which should be aimed at very early stages of the disease before threshold beta-amyloid concentration is reached for plaque deposition,” he told us.
Study offers ‘compelling’ evidence of neurodegeneration mechanism
Bryen Jordan, PhD , a professor of neuroscience and of psychiatry and behavioral sciences at the Albert Einstein College of Medicine, not involved in the study, told MNT that “this study represents a significant and somewhat eye-opening contribution to Alzheimer’s disease research as it challenges the long-standing neuron-centric view of beta-amyloid production.”
“The study shows in a compelling manner that oligodendrocytes not only express the amyloid precursor protein (APP) and related processing enzymes, but also contribute up to 30% of the brain’s beta-amyloid load. This is very surprising and underscores the need to revisit the basic biology of APP and beta-amyloid, particularly given the high-profile failures of therapies targeting neuronally derived beta-amyloid peptides.”
– Bryen Jordan, PhD
“Such findings should help redirect a larger portion of the nearly $3.8 billion in annual Alzheimer’s funding to research involving glial cells,” Jordan noted.
Moreover, he added, “[t]his study reinforces an emerging body of work that is rapidly reshaping our understanding of oligodendrocytes.”
“Traditionally viewed as important only during development for myelination, oligodendrocytes are now recognized as key regulators of higher order brain functions such as, learning, memory, and addiction, and potentially key players in neurodegenerative diseases like Alzheimer’s disease.”
– Bryen Jordan, PhD
Future implications for Alzheimer’s research
“Identifying oligodendrocytes as significant contributors to beta-amyloid production should open up new avenues for therapeutic development that could target these glial cells alongside neurons,” Jordan explained.
“While the impacts for patient care are more moderate, this research suggests that white matter abnormalities previously observed in Alzheimer’s patients may play a more primary role in pathophysiology, rather that represent an epiphenomena,” he added, noting that “[t]his view could result in the adoption of myelin-regulating therapies being developed for disease traditionally associated with myelin pathology such as multiple sclerosis.”
Jordan concluded that, “by expanding the focus of Alzheimer’s research to include glial cells, this study may help overcome the limitations of previous therapies.”
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