Myelin Pathology in Alzheimer's Disease Models

Myelin integrity is increasingly recognised as a critical factor in Alzheimer’s disease pathogenesis. In transgenic mouse models, structural defects in the myelin sheath emerge with advancing age and correlate with amyloid-β accumulation, neuroinflammation and cognitive decline. Myelin disruption not only compromises axonal conduction and energy support but also appears to redirect microglial activity from plaque clearance to sites of myelin damage. Oligodendrocyte lineage cells—ranging from progenitors to mature myelinating cells—undergo morphological and functional remodelling in response to amyloid pathology, suggesting a bidirectional interplay between amyloidogenic processes and white matter degeneration. Together, these findings point to myelin pathology as both an upstream driver and a downstream consequence of Alzheimer-like changes, offering new avenues for early intervention and myelin-targeted therapies.

Research from Nature Portfolio

Recent studies have demonstrated that genetically induced myelin dysfunction in Alzheimer’s mouse models accelerates amyloid plaque formation by promoting the local accumulation of amyloid-generating enzymes within axonal swellings and by diverting microglial clearance away from plaques towards myelin lesions. Complementary work has revealed that oligodendrocytes themselves are a significant source of amyloid-β: selective deletion of β-secretase in these cells reduces plaque burden, indicating that oligodendroglial amyloid production contributes directly to disease progression. These insights position myelin integrity and oligodendrocyte-derived amyloid-β as upstream modulators of Alzheimer’s pathology and highlight novel cellular targets to slow onset and ameliorate cognitive deficits.

Myelin Pathology in Alzheimer's Disease Models publication trend

The graph below shows the total number of articles in myelin pathology in alzheimer's disease models across all publications each year (not limited to Nature Index journals).

Technical terms

Myelin: Lipid-rich insulating sheath around axons that enables rapid nerve impulse conduction and supports axonal metabolism.

Oligodendrocyte: Glial cell in the central nervous system responsible for the formation and maintenance of myelin sheaths.

Oligodendrocyte progenitor cell (OPC): Precursor cell that proliferates and differentiates into myelinating oligodendrocytes throughout life.

Amyloid-β (Aβ): Peptide fragment derived from amyloid precursor protein prone to aggregation, forming plaques characteristic of Alzheimer’s pathology.

Microglia: Resident immune cells of the central nervous system that survey the environment, clear debris and mediate inflammatory responses.

References

1. Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease. Nature (2023).
2. Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer’s disease model mice. Nature Neuroscience (2024).
3. Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer's disease. Neurobiology of Aging (2020).
4. Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination. Molecular Neurodegeneration (2022).