Demyelination Accelerates Amyloid-β Aggregation

Nerves require myelin sheathing in order to function correctly. With age, some degree of dysfunction in myelin maintenance takes place, with consequent cognitive and other nervous system degeneration as a consequence. This loss of myelin integrity takes place to a lesser degree than is the case in severe demyelinating conditions such as multiple sclerosis. Nonetheless, that lesser degree may be contributing to the early stages of Alzheimer's disease by reducing immune clearance of amyloid-β aggregates.

At present a question hovers over the role of amyloid-β in Alzheimer's disease due to the failure of amyloid-clearing immunotherapies to improve patient outcomes in the clinic. The research and development communities remain largely wedded to the idea that amyloid-β aggregation will turn out to be relevant to the early onset of the condition, but it remains to be seen as to whether even that is correct, accepting that the later stages have moved on to other primary mechanisms of harm associated with neuroinflammation and tau aggregation.

Poorly insulated nerve cells promote Alzheimer's disease in old age

Intact myelin is critical for normal brain function. Researchers have shown that age-related changes in myelin promote pathological changes in Alzheimer's disease. 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 (Aβ). The Aβ 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. Researchers 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 Aβ.

At the same time, the myelin defects attract the attention of the brain's immune cells called microglia. 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.

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.