Myelin aging: A new perspective on the progression of Alzheimer’s disease

summary: Age-related degeneration of myelin, the insulating layer surrounding neurons in the brain, actively drives disease-associated changes in Alzheimer’s disease.

The researchers examined Alzheimer’s disease mouse models with myelin defects and found that these defects promoted the formation of amyloid plaques, a hallmark manifestation of Alzheimer’s disease. Defects in myelin also appear to overwhelm immune cells in the brain called microglia, diverting focus from plaque removal.

These findings may open new strategies for the prevention and treatment of Alzheimer’s disease by targeting myelin damage.

Important facts:

1. Age-related myelin degeneration in the brain may actively drive Alzheimer’s disease.
2. Loss of myelin promotes the formation of amyloid plaques, a hallmark of Alzheimer’s disease.
3. The immune cells of the brain, microglia, are redirected by myelin deficiency, making plaque clearance less effective.

sauce: Max Planck Institute

Alzheimer’s disease, an irreversible form of dementia, is considered the most common neurodegenerative disease in the world.

the main risk factor for Alzheimer’s disease I don’t know why, but it’s age. The insulating layer called myelin, which surrounds nerve cells in the brain, is known to degenerate with age.

Researchers at the Max Planck Institute for Interdisciplinary Sciences (MPI) in Göttingen have shown that such deficient myelin actively promotes disease-associated changes in Alzheimer’s disease.

Delaying age-related myelin damage may open new ways to prevent or slow the progression of this disease in the future.

what was i trying to do? Where did you put your keys? When was that appointment? It begins with slight amnesia, making it difficult to orient, follow a conversation, articulate, or perform simple tasks.

In the final stages, patients are most often dependent on caregivers. Alzheimer’s disease progresses slowly and mainly affects the elderly. His risk of developing Alzheimer’s disease doubles every five years after age 65.

signs of brain aging

“The underlying mechanisms that explain the correlation between age and Alzheimer’s disease remain to be elucidated,” says Klaus Armin Naab, director of the MPI for Multidisciplinary Sciences.

With a team in the Department of Neurogenetics, he studies the function of myelin, the lipid-rich insulating layer of nerve cell fibers in the brain. Myelin ensures rapid communication between nerve cells and supports nerve cell metabolism.

“Intact myelin is critical for normal brain function. We have shown that age-related changes in myelin drive the pathological changes in Alzheimer’s disease,” says Nave.

A new study now published in the journal Nature, scientists investigated the possible role of age-related myelin degradation in the development of Alzheimer’s disease. Their research focused on the typical features of this disease.

“Alzheimer’s disease is characterized by the deposition of a specific protein in the brain, the so-called amyloid beta peptide, or Aꞵ peptide for short,” said Constanze Depp, one of the two lead authors of the study. says.

“Aβ peptides aggregate to form amyloid plaques. In patients with Alzheimer’s disease, these plaques form years and even decades before the first symptoms appear.” , eventually resulting in irreversible death of nerve cells and impaired communication in the brain.

Researchers used imaging and biochemical techniques to examine and compare different mouse models of Alzheimer’s disease, which develop amyloid plaques similar to Alzheimer’s disease patients.

But for the first time, they studied Alzheimer’s mice with the addition of myelin defects that occur in the human brain as we age.

Ting Sun, the study’s second lead author, explains the results: Defective myelin stresses nerve fibers, causing them to swell and produce more Aꞵ peptides. “

Overwhelming immune cells

At the same time, myelin deficiency attracts the attention of immune cells in the brain called microglia.

“These cells are very vigilant and watch the brain for signs of damage. They can pick up and destroy dead cells, cellular components and other materials,” Depp said. added.

Normally, microglia detect and remove amyloid plaques, preventing their accumulation. However, when microglia are confronted with both deficient myelin and amyloid plaques, microglia primarily clear myelin remnants while plaques continue to accumulate.

Researchers suspect that microglia may be “distracted” or overwhelmed by myelin damage and unable to respond appropriately to plaque.

The results of this study show for the first time that myelin defects in the aged brain increase the risk of Aβ peptide deposition.

“We hope this will lead to new treatments. If we succeed in slowing the age-related damage to myelin, we may be able to prevent or slow down Alzheimer’s disease,” says Nave.

About this Alzheimer’s Disease Research News

author: Klaus Armin Nave
sauce: Max Planck Institute
contact: Klaus Armin Nave – Max Planck Institute
image: Image credited to Neuroscience News

Original research: open access.
“Myelin dysfunction promotes amyloid-β deposition in an Alzheimer’s disease modelby Klaus Armin Nave et al. Nature

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overview

Myelin dysfunction promotes amyloid-β deposition in an Alzheimer’s disease model

Although the incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, it is still poorly understood why age constitutes a major risk factor.

Brain aging affects the structural integrity of oligodendrocytes and myelin sheaths, which are associated with secondary neuroinflammation.

Because oligodendrocytes support axonal energy metabolism and neuronal health, loss of myelin integrity is associated with neuronal amyloid-β (Aβ) deposition, a central neuropathological hallmark of Alzheimer’s disease. We hypothesized that it may be an upstream risk factor for

Here we identify genetic pathways of myelin dysfunction and demyelinating injury as potent drivers of amyloid deposition in a mouse model of Alzheimer’s disease. Mechanistically, myelin dysfunction causes accumulation of her Aβ-producing machinery within axonal swelling and increased cleavage of cortical amyloid precursor protein.

Strikingly, AD mice with myelin dysfunction lack plaque-surrounding microglia, despite their increased overall numbers.

Bulk and single-cell transcriptomics of AD mouse models with myelin deficiency show that there is co-induction of highly similar but distinct disease-associated microglial signatures specific for myelin damage and amyloid plaques, respectively.

Despite successful induction, amyloid disease-associated microglia (DAM), which normally clear amyloid plaques, are apparently distracted by nearby myelin damage.

Our data suggest a working model in which age-dependent structural defects in myelin directly and indirectly promote Aβ plaque formation and are thus upstream AD risk factors. Improving oligodendrocyte health and myelin integrity may be promising targets for delaying the onset and slowing progression of AD.