As the brain ages, the insulating myelin sheath around axons begins to degrade. Could this white-matter degeneration trigger Alzheimer’s disease? In a preprint on bioRXiv, researchers led by Constanze Depp and Klaus-Armin Nave at the Max Planck Institute of Experimental Medicine in Göttingen, Germany, suggest as much. In mouse models of amyloidosis, myelin damage accelerated plaque formation, while a lack of myelin delayed it. The authors identified two mechanisms linking myelin to plaques in mouse brain. One, damaged myelin drove production of Aβ, directly leading to deposits; two, microglia appeared to preferentially mop up degenerating myelin, ignoring plaques and allowing them to grow. The data hint that myelin damage could tip a brain toward AD, and may even explain why Alzheimer’s risk increases with age, Depp told Alzforum. If the finding holds in people, it will imply that protecting myelin could help prevent AD, she added.
- Myelin defects speed up amyloid deposition in mice, while lack of myelin delays it.
- Degenerating myelin drives Aβ production.
- Damaged myelin distracts microglia from plaques.
Others said the data advance the field. “This fascinating paper by Depp et al. greatly advances our understanding of how oligodendrocytes contribute to AD,” Mikael Simons at Technical University Munich, Germany, wrote to Alzforum (full comment below). Barbara Bendlin at the University of Wisconsin, Madison, pointed to previous hints connecting myelin to Alzheimer’s pathology. “The results greatly strengthen the myelin/AD link, and will be highly encouraging to researchers focused on understanding white-matter abnormalities in AD,” she wrote (comment below).
Plaque Pusher. 5xFAD mice with myelin defects (right) develop 50 percent more cortical plaques (white) than do 5xFAD controls (left). [Courtesy of Depp et al., bioRXiv.]
Researchers have long known that myelin frays during aging, and even more in AD brain (Roher et al., 2002; Stricker et al., 2009; Bowley et al., 2010). Notably, brain regions that start out with the thinnest myelin, such as the frontal cortex, are also the most vulnerable to amyloid pathology (Braak and Braak, 1997). The late George Bartzokis, when he was at the University of California, Los Angeles, proposed a “myelin model” of the brain, in which amyloid deposits might be a by-product of myelin repair (Bartzokis, 2011). Supporting a link, a recent study by Bendlin and colleagues correlated myelin deterioration with Alzheimer’s cerebrospinal fluid biomarkers in people at risk for cognitive decline, implying that white-matter damage could be an early sign of the disorder (Nov 2016 news).
This body of research led the researchers in Germany to ask if myelin deterioration could drive amyloidosis. To explore this, joint first authors Depp and Ting Sun used two myelin mouse models developed in their lab. In one, knockout of the key myelin component proteolipid protein 1 (PLP1) renders the insulating sheath unstable and prone to break down with age (Klugmann et al., 1997). In the other, knockout of the enzyme 2',3'-cyclic nucleotide 3' phosphodiesterase (CNP) prevents oligodendrocytes from metabolically supporting axons. As a consequence, portions of the axon swell up and neurons die (Lappe-Siefke et al., 2003). The authors reasoned that these knockouts might mimic subtle myelin defects that occur with age.
They crossed these mice with 5xFAD mice. At six months of age, 5xFAD mice have widespread cortical plaques. Lack of either PLP1 or CNP worsened this, with 50 percent more plaques in the cortex (see image above). The effect was more pronounced in white matter. In the alveus, a tract overlying the hippocampus, more than twice as many plaques speckled the tissue. This was not a quirk of the 5xFAD model; the authors found a similar boost in plaque formation when they crossed APPNLGF knock-ins with CNP knockouts.
Demyelination Triggers Plaque. In 5xFAD mice injected with a demyelinating agent (right), more plaques (purple) form in the alveus tract than in 5xFAD controls (left). Nuclei are blue. [Courtesy of Depp et al., bioRXiv.]
Other experiments strengthened the evidence. Treating young 5xFAD mice with the demyelinating agent cuprizone boosted plaques in the alveus fourfold (see image above). Likewise, injecting young 5xFAD mice with myelin oligodendrocyte glycoprotein (MOG) to induce demyelination in the spinal cord triggered robust plaque formation around the lesion. Conversely, crossing 5xFAD mice with transgenic mice that lack forebrain myelin delayed plaque formation there by three months.
How does malfunctioning myelin promote amyloidosis? Possibly by boosting Aβ production. In 5xFAD/CNP-/- crosses, swollen myelin around plaques contained about 50 percent more amyloidogenic APP cleavage products and Aβ than did myelin in 5xFAD controls, suggesting more Aβ was made near damaged myelin. Other studies have linked disrupted axonal transport to amyloid production (Oct 2016 conference news; Mar 2017 news; Gowrishankar et al., 2017).
However, microglia changes seemed to play a role as well. In 5xFAD and APPNLGF mice sans CNP, microglia failed to surround plaques. This was reminiscent of TREM2 knockouts, in which microglia lose the ability to corral amyloid (Aug 2017 news; Jan 2019 news). To the authors’ surprise, however, RNA sequencing showed that TREM2 induction was unchanged by loss of CNP. Moreover, microglia in 5xFAD/CNP-/- turned up expression of other disease-associated microglia (DAM) genes even higher than did cells in 5xFAD controls.
Why, then, did they not surround plaques? Perhaps because they were distracted by myelin debris. Depp noted that myelin decays before plaques form in 5xFAD/CNP-/- mice, so microglia may become specialized for myelin cleanup and unable to respond to plaque. In one sign of this, these cells expressed many genes involved in metabolizing lipids, which are abundant in myelin. The microglia appeared similar to the recently described white-matter-associated microglia, Depp said (Mar 2021 news).
Next, the authors want to figure out which mechanism predominates. They will try to parse oligodendrocyte and microglia effects by using myelin mutants that do not activate microglia, and by depleting microglia from 5xFAD/CNP-/- mice. Depp is also interested in the role of tau pathology, and is crossing tauopathy models with the myelin mutants.
Does all this happen in human brain? The authors found a large number of activated microglia among deteriorating myelin in postmortem AD brain, but not in age-matched controls (see image at right). In addition, a previous analysis of gene expression around plaques in postmortem AD brain had shown a decrease in myelination genes, again invoking a connection between myelination and plaques (Jul 2020 news).
It is unclear if demyelinating diseases such as multiple sclerosis lead to AD, since until recently people with these conditions did not live long enough to develop diseases of aging. One recent review notes several cases of people with both disorders, but the relative risk of AD in MS patients is unknown (Luczynski et al., 2019). However, cognitive decline is common, affecting more than half of MS patients (National MS Society).
If myelin dysfunction does increase AD risk, would not healthy myelin help stave off the disease? Depp noted that many behaviors that lower AD risk, such as exercise and eating a Mediterranean diet rich in fish oil, are known to benefit myelin (Apr 2006 news; Aug 2016 news; Apr 2017 conference news). On the other hand, environmental factors that damage myelin, such as traumatic brain injury, are associated with a higher risk of AD (Sep 2016 news; May 2018 news).
Could interventions that promote myelination, such as drugs for multiple sclerosis, help keep the brain healthy? Depp is encouraged by recent research showing that administering a myelin-promoting drug to APP/PS1 mice improved their memories and learning abilities (Chen et al., 2021). “Those data were stunning. It’s the other side of the coin from our study, and fits it perfectly,” Depp said.—Madolyn Bowman Rogers
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- New Myelin Makes Memories, but Supply Wanes with Age
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