Alzheimer's disease (AD) is a neurodegenerative disease but also associated with changes in the white matter of the brain which does not contain nerve cells but myelinated axons. Myelin is a lipid-rich layer that insulates neuronal processes. It is formed throughout life in the central nervous system (brain and spinal cord) by one variety of glial cells, the oligodendrocytes, which arise from specific progenitor cells (OPCs). As discussed last week here on the blog, myelinization is relevant in old age mainly because its stimulation promotes memory functions.
As we age, myelin production declines, and a number of abnormalities are found in the white matter of Alzheimer's patients. However, it is still unclear whether the changes observed in histological and imaging studies are directly involved in the pathogenesis of AD or are a consequence of neurodegeneration. A study by Chen and colleagues from Chongqing, China, and San Fancisco, USA, addressed this question in an APP/PS1 mouse model of AD. In these transgenic animals, high levels of amyloid precursor protein (APP) and presenilin (a subunit of the APP-cleaving γ-secretase) are found. The mice produce increased Aβ-peptides and amyloid deposits (see also section 2.3.2 in my book on neurodegeneration).
Chen et al. studied the breakdown and degradation of myelin, whose protein components were visualized by special green fluorescent protein (GFP) in OPCs and oligodendrocytes. Interestingly, the amount of newly formed myelin sheaths was significantly higher in 8-month-old AD mice than in control mice. Amyloid deposition was barely detectable in the GFP-positive myelin-containing areas. The total amount of myelin was reduced in APP/PS1 mice compared with control animals at 8 and 13 months of age (coincident with cognitive decline) but not at 4 months. In addition, electron microscopy examination showed a marked decrease in myelinated axons in APP/PS1 mice compared with wild-type mice (at 17 and 22 months of age).
Finally, the researchers led by Feng Mei showed that the amount of myelin basic protein (MBP) in tissue sections of cortex and hippocampus was also reduced in Alzheimer's disease patients as compared with age-matched controls. They also addressed the therapeutically relevant question of whether stimulating myelin production could remedy the cognitive deficits in elderly APP/PS1 mice. To this end, an inducible and conditional knockout of the gene Chrm1, which is an inhibitor of OPC differentiation, demonstrated increased formation of mature oligodendrocytes and increased formation of myelin sheaths in 7-8-month-old APP/PS1 mice. Silencing Chrm1 also resulted in significant performance improvements in memory-related tasks and novel object recognition.
In light of these findings, the authors then tested whether pharmacological enhancement of myelination could reverse myelin sheath loss and cognitive deficits in AD mice. They treated 8-month-old APP/PS1 mice with clemastine, an activator of OPC differentiation approved for the treatment of allergy. Compared with control animals, treatment with clemastine enhanced myelin formation and improved performance on cognitive tests. It was also confirmed that Aβ deposition or microglial clearance of plaques was not affected by clemastine treatment, suggesting that the cognitive improvements were a direct consequence of promoting myelin renewal.
In summary, myelin destruction is an important feature of Alzheimer's disease. Endogenous myelin repair is apparently not sufficient to prevent the loss of myelin. Apparently, this contributes to the cognitive decline in AD, so promoting the regeneration of myelin may be a useful treatment strategy in the future.
References:
Chen J-F, Liu K, Hu B, Li R-R, Xin W, Chen H, Wang F, Chen L, Li R-X, Ren S-Y, Xiao L, Chan JR, Mei F. (2021) Enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer's disease. Neuron 109:2292
Otto G. (2021) Repairing nerve damage. Nature Reviews Neuroscience 22:456
Image credit: iStock/wildpixel
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