Discovery of new glial cell function sheds light on neurodegenerative diseases
Mammalian brain cells mostly comprise neurons and glial cells. The complex network of neurons communicates by sending signals along thin nerve fibres called axons. The speed at which axons conduct these electrical impulses is enhanced by a fatty insulating sheath called myelin. The MyeliNANO project, supported by the European Research Council, wanted to better understand the contribution of specialised glial myelin-making cells, called oligodendrocytes, to the brain’s information processing. “Our experiments with novel transgenic mice suggest that a key role for oligodendrocytes is not only to speed up the transmission of electrical impulses but, perhaps more importantly, to metabolically support axons,” says Klaus-Armin Nave, project coordinator. “This discovery is relevant for multiple sclerosis, but also for neuronal disorders like Alzheimer’s disease.” The project has generated a number of journal publications, with more under review and/or revision, alongside dissemination at major conferences, including a Nobel Symposium on myelin in Stockholm and at the European Society for Neurochemistry, where Nave will also give a keynote address later this year in St Petersburg.
Hypomorphic mice models
The team genetically altered mice so that their forebrains’ oligodendrocytes could not make myelin but could continue supporting axons metabolically. This was achieved by genetically targeting the common forebrain stem cells of neurons and glia, using the regulatory elements of the Emx1 gene, to express a bacterial recombinase gene that deactivates a critical gene for myelin formation. As the spinal cord and cerebellum oligodendrocytes still myelinated normally, movement-dependent behaviours – such as navigation – could be observed to determine the impact of lost forebrain myelination on higher brain functions, such as learning and memory. “Surprisingly, the absence of forebrain myelin didn’t impact mouse behaviour as expected. Even specialised tests did not reveal major loss of cognitive function. This suggests that cognitive decline in humans linked to lost myelin is unlikely to be due to slowed electronic impulses but rather compromised axonal metabolism which blocks conduction,” explains Nave. To study the effect of brain ageing – including myelin ageing – on Alzheimer’s disease, the team analysed amyloid deposition in the brains of transgenic mice with this disease. 5XFAD mice were cross-bred to a strain of myelin mutants exhibiting premature brain white matter myelin ageing, due to a lack of specific myelin proteins causing loss of axonal integrity and neuroinflammation. The result – as hypothesised – was an earlier onset of Alzheimer’s-like symptoms, documented with a novel method of whole brain histopathology, using light sheet microscopy. “Amyloidosis, the hallmark of Alzheimer’s disease, seems linked to a failure of ageing oligodendrocytes to maintain myelin and neuronal integrity. Ageing myelin also seems to hamper microglial cells removing newly formed amyloid plaques,” summarises Nave. Additional experiments with hypomyelinated mice challenged the theory that axonal degeneration in multiple sclerosis lesions is simply due to lost myelin. The team found in multiple sclerosis mouse models that axon damage was more prevalent in myelinated than in unmyelinated nerve fibres. “This suggests that it is the injured oligodendrocytes’ failure to support myelinated axons that is crucial; presumably because the nanochannels through which oligodendrocytes provide essential nutrients to axons are destroyed,” adds Nave. Using electron-microscopic techniques and 3D modelling, the team reconstructed this nanochannel system for visualisation. “Our work changes how we think about myelinating glial cells and myelin diseases. It is rare to discover a new cellular function relevant to human diseases,” concludes Nave.
Keywords
MyeliNANO, myelin, neuron, glial, brain, axon, Alzheimer’s disease, multiple sclerosis, neurodegenerative, oligodendrocytes, metabolic
