Summary: Age-related degeneration of myelin, the insulating layer around nerve cells in the brain, actively promotes disease-related changes in Alzheimer’s.
Researchers examined mouse models of Alzheimer’s with myelin defects, finding that these defects accelerated the formation of amyloid plaques, a characteristic sign of Alzheimer’s. The defective myelin also seemingly overwhelmed the brain’s immune cells, called microglia, diverting their focus from plaque removal.
These findings could open up new strategies for Alzheimer’s prevention and treatment by targeting myelin damage.
- Age-related myelin degeneration in the brain may actively promote Alzheimer’s disease.
- Defective myelin accelerates the formation of amyloid plaques, which are characteristic of Alzheimer’s.
- Microglia, the brain’s immune cells, are diverted by myelin defects, reducing their effectiveness in plaque removal.
Source: Max Planck Institute
Alzheimer’s disease, an irreversible form of dementia, is considered the world’s most common neurodegenerative disease.
The prime risk factor for Alzheimer’s is age, although it remains unclear why. It is known that the insulating layer around nerve cells in the brain, named myelin, degenerates with age.
Researchers at the Max Planck Institute (MPI) for Multidisciplinary Sciences in Göttingen have now shown that such defective myelin actively promotes disease-related changes in Alzheimer’s.
Slowing down age-related myelin damage could open up new ways to prevent the disease or delay its progression in the future.
What was I about to do? Where did I put the keys? When was that appointment again? It starts with slight memory lapses, followed by increasing problems to orient, to follow conversations, to articulate, or to perform simple tasks.
In the final phase, patients are most often care-dependent. Alzheimer’s disease progresses gradually and mainly affects the elderly. The risk of developing Alzheimer’s doubles every five years after the age of 65.
Signs of aging in the brain
“The underlying mechanisms that explain the correlation between age and Alzheimer’s disease have not yet been elucidated,” says Klaus-Armin Nave, director at the MPI for Multidisciplinary Sciences.
With his team of the Department of Neurogenetics, he investigates the function of myelin, the lipid-rich insulating layer of the brain’s nerve cell fibers. Myelin ensures the rapid communication between nerve cells and supports their metabolism.
“Intact myelin is critical for normal brain function. We have shown that age-related changes in myelin promote pathological changes in Alzheimer’s disease,” Nave says.
In a new study now published in the journal Nature, the scientists explored the possible role of age-related myelin degradation in the development of Alzheimer’s. Their work focused on a typical feature of the disease.
“Alzheimer’s is characterized by the deposition of certain proteins in the brain, the so-called amyloid beta peptides, or Aꞵ peptides for short,” states Constanze Depp, one of the study’s two first authors.
“The Aꞵ peptides clump together to form amyloid plaques. In Alzheimer’s patients, these plaques form many years and even decades before the first symptoms appear.” In the course of the disease, nerve cells finally die irreversibly and the transmission of information in the brain is disturbed.
Using imaging and biochemical methods, the scientists examined and compared different mouse models of Alzheimer’s in which amyloid plaques occur in a similar way to those in Alzheimer’s patients.
For the first time, however, they studied Alzheimer’s mice that additionally had myelin defects, which also occur in the human brain at an advanced age.
Ting Sun, second first author of the study, describes the results: “We saw that myelin degradation accelerates the deposition of amyloid plaques in the mice’ brains. The defective myelin stresses the nerve fibers, causing them to swell and produce more Aꞵ peptides.”
Overwhelmed immune cells
At the same time, the myelin defects attract the attention of the brain’s immune cells called microglia.
“These cells are very vigilant and monitor the brain for any sign of impairment. They can pick up and destroy substances, such as dead cells or cellular components,” Depp adds.
Normally, microglia detect and eliminate amyloid plaques, keeping the buildup at bay. However, when microglia are confronted with both defective myelin and amyloid plaques, they primarily remove the myelin remnants while the plaques continue to accumulate.
The researchers suspect that the microglia are ‘distracted’ or overwhelmed by the myelin damage, and thus cannot respond properly to plaques.
The results of the study show, for the first time, that defective myelin in the aging brain increases the risk of Aꞵ peptide deposition.
“We hope this will lead to new therapies. If we succeeded in slowing down age-related myelin damage, this could also prevent or slow down Alzheimer’s disease,” Nave says.
About this Alzheimer’s disease research news
Original Research: Open access.
“Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease” by Klaus-Armin Nave et al. Nature
Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease
The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood.
Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths, the latter of which is associated with secondary neuroinflammation.
As oligodendrocytes support axonal energy metabolism and neuronal health, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-β (Aβ) deposition, the central neuropathological hallmark of AD.
Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aβ-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein.
Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers.
Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively.
Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage.
Our data suggest a working model whereby age-dependent structural defects of myelin promote Aβ plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.