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Scientists solve the mysteries of why and how brain cells die from Alzheimers

[Sept. 22, 2023: Staff Writer, The Brighter Side of News]

Alzheimer's disease is not a standalone anomaly but a prominent subtype of a group of cognitive disorders known as dementia. (CREDIT: Creative Commons)

In the sprawling labyrinth of Alzheimer's research—a field dotted with setbacks and limited successes—scientists have been left grappling with a multitude of questions about the underlying processes of this neurodegenerative disease. One of the most confounding aspects has been understanding why brain cells die.

This long-standing conundrum has kept researchers on the edge of discovery and despair for decades. However, groundbreaking new research promises to change this narrative, and the first wave of optimism is tied to the recently FDA-approved drug, Lecanemab, as well as discoveries related to abnormal proteins and cell death in Alzheimer's patients.


The Global Prevalence and the Growing Crisis

Before delving into the latest scientific revelations, it's critical to set the stage by highlighting the enormity of the issue at hand. Alzheimer's disease is not a standalone anomaly but a prominent subtype of a group of cognitive disorders known as dementia. Across the globe, approximately 55 million people are living with some form of dementia.

MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease. (CREDIT: Science)

Disturbingly, two-thirds of these individuals are in developing countries. As the world's population continues to age, estimates suggest that the number of dementia cases will skyrocket to about 139 million by 2050. Countries in China, India, Latin America, and Sub-Saharan Africa are projected to bear the brunt of this health crisis.


Decades of research have yielded limited success in developing effective treatments for Alzheimer's. The disease is notorious for its complexity and its ability to elude complete scientific understanding. Researchers have identified various proteins—most notably amyloid and tau—that manifest in the brain as the disease progresses. Despite this, the interaction between these proteins and their role in the devastation of neural pathways remains inadequately understood.

Integration of the transplanted neurons in the Rag2-/- animals. Coronal section of 18-months old grafted mouse brain showing the graft location (green, indicated with white arrows). Scale bar 1000 µm. Higher magnification image of neuronal process displaying dendrites and mature spines (right boxes). White arrows indicates dendritic spines. Scale bar 10 µm. (CREDIT: Science)

"It's been difficult to develop medicines against Alzheimer's because researchers have yet to fully understand what happens in the brain when the disease takes hold," says Bart De Strooper of the Dementia Research Institute in the UK.


Breaking Down the Complexities of Brain Cell Death

However, new research is starting to clear the fog surrounding this critical issue. According to a recent study published in the journal Science, scientists based in Belgium and the UK have established a direct connection between these abnormal proteins—amyloid and tau—and a process known as necroptosis, otherwise referred to as programmed cell death.

Characterization of the 18 months old grafted animals. Quantification of the number of host microglia around the Aβ plaque, within 20 microns diameter (n=4, >100 plaques/mice). (B) Quantification of the number of host astrocytes around the Aβ plaque, within 20 microns diameter (n=4, >100 plaques/mice). (CREDIT: Science)

Typically, cell death is a natural, beneficial process. When cells die off, usually due to an immune response to infection or inflammation, it allows for the regeneration of new, healthy cells. However, in the context of Alzheimer's, this process takes a disastrous turn.


Unveiling the Mechanisms of Cell Death

Researchers propose that brain cells in Alzheimer's patients become inflamed due to the infiltration of amyloid proteins into neurons. This infiltration alters the internal chemistry of the cells, triggering a sequence of harmful events. The amyloid proteins clump together, forming dense plaques, while tau proteins create fibrous bundles, known as tau tangles. These formations in turn lead to the production of a molecule named MEG3.

Characterization of 18 months old non-grafted animals. (A) Representative confocal images of non-grafted 18 months old control (top) (n=4) and amyloid mice (bottom) (n=4) showing the glial reaction. Amyloid (X34, blue), microglia (IBA1, red), Astrocytes (GFAP, grey). Scale bar 30 µm. (CREDIT: Science)

"In the study, the researchers attempted to block MEG3 and found that when they were able to block it, the brain cells survived," explains Bart De Strooper. "It was the first time—after 30-40 years of speculation—that scientists had found a possible explanation for cell death in Alzheimer's patients."


The Promise of Lecanemab: A New Era in Alzheimer’s Treatment?

This breakthrough opens up promising avenues for the development of new medications that could halt or even reverse the progress of Alzheimer's. Here's where the newly approved drug, Lecanemab, becomes pivotal.

Approved for use by the US Food and Drug Administration in 2023, Lecanemab has shown encouraging signs of slowing down the early stages of Alzheimer’s disease by specifically targeting the amyloid protein.


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Researchers are optimistic that if they can successfully block the MEG3 molecule, it could potentially stop cell death altogether, providing an immensely promising avenue for treatment.

"The researchers, based at KU Leuven in Belgium and the Dementia Research Institute of University College London, said they hope their findings will help in the discovery of new medical treatments for Alzheimer's patients," says Bart De Strooper. "Their hope is not without good reason: the drug Lecanemab specifically targets the protein amyloid. If it's possible to block the MEG3 molecule, medicine may manage to stop cell death in the brain altogether."


Beyond Lecanemab: The Future of Alzheimer's Research

The research journey is far from over, but these recent discoveries signify a new epoch in Alzheimer's research and treatment. The pathway to blocking MEG3 may eventually provide a means to halt the disease’s devastating progression, giving hope to millions of affected individuals and their families worldwide.

Characterization of Tau pathology and necroptosis signatures in 6-months old animals grafted with mouse NPCs. Schematic representation of the mouse neural progenitors' cells differentiated from the mouse embryonic stem cell line (E14 cell line, GFP positive) following the protocols published in Gaspard et al 2009. (CREDIT: Science)

Coupled with advanced methods of early detection and the advent of more targeted therapies, the findings related to abnormal proteins and cell death may finally offer a glimmer of hope in a field that has, for far too long, been steeped in uncertainty and disappointment. While scientists acknowledge that there's still a long way to go, the paradigm is undoubtedly shifting.


Through the continuing efforts of the global research community, the momentum is expected to build, leveraging the combined insights from new pharmacological approaches, the unraveling of molecular mechanisms, and advanced brain imaging techniques. Collectively, these will forge a multi-pronged attack against Alzheimer’s, aimed not just at alleviating symptoms but at striking at the very root of the disease.

In the end, what these revelations point to is not just the potential for groundbreaking treatment methods, but a fundamental change in our understanding of Alzheimer's and, by extension, dementia. As we navigate through this exciting period of discovery, we may well be on the cusp of turning the tide against one of the most debilitating diseases known to humanity.

For more science news stories check out our New Innovations section at The Brighter Side of News.


Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.


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