Studies in mice have shown how cells called microglia may help to prevent the secondary progressive phase of multiple sclerosis (MS) by clearing dead cell debris, including myelin, from the central nervous system (CNS). Headed by scientists at the Karolinska Institutet, the research, in a mouse model of MS, found that this process of debris clearance—known as autophagy—was interrupted when a gene called Atg7 was removed from the microglia.

The experiments also showed that treating mice using the plant-derived sugar, trehalose, induced autophagy in microglial cells, and was associated with disease remission. “The treatment with trehalose shows that microglial cells can be targeted for beneficial purposes with a compound already found in plant- and fungi-derived diets—and thereby likely not toxic,” said Rasmus Berglund, doctoral student and lead author of the team’s published study. “This gives an option not only to use these findings as treatment of established disease but also the possibility of pro-active diet recommendations.”

Berglund and colleagues reported on their findings in Science Immunology, in a paper titled, “Microglial autophagy-associated phagocytosis is essential for recovery from neuroinflammation.”

MS is a chronic inflammatory disease of the CNS and one of the main causes of neurological functional impairment. The disease is generally diagnosed between 20 and 30 years of age, and can lead to severe neurological symptoms, such as loss of sensation and trembling, difficulties walking and maintaining balance, memory failure, and visual impairment. In the majority of cases, MS manifests as bouts with a certain amount of subsequent recovery. A gradual loss of function with time is, however, inevitable. Yet while disease progression is “the most clinically challenging” aspect of MS, it is also “the least mechanistically explored,” the investigators wrote.

Research group, from the left: André Ortlieb Guerreiro-Cacais (researcher), Maja Jagodic, PhD, (docent and group leader for research on MS epigenetics), Rasmus Berglund (doctoral student), and Tomas Olsson (professor). [Ulf Sirborn]
Research has led to progress in treatments that reduce the frequency and damaging effects of these bouts, but they are not a cure. “Despite these important breakthroughs, the disease generally worsens when the patient has had it for 10 to 20 years,” said research lead Maja Jagodic, PhD, docent of experimental medicine at the department of clinical neuroscience and the Centre for Molecular Medicine, at the Karolinska Institutet.

“There is currently only one, recently approved, treatment for what is called the secondary progressive phase. The mechanisms behind this progressive phase require more research.”

Age is the strongest risk factor for developing progressive MS and many age-associated neurodegenerative diseases. Many other age-associated neurodegenerative pathologies, including Alzheimer’s disease, and autoinflammatory diseases such as Crohn’s disease, and systemic lupus erythematosus (SLE), are characterized by impaired autophagy, the process by which cells normally break down and recycle their own proteins and other structural components, including myelin in nerve cells.

Administration of trehalose to aged mice (right) increased the nuclear density of TFEB (purple), a transcription factor controlling cellular debris clean up, and LAMP1 (yellow), a major organelle component of inner cells, inside microglia. Data pooled from two experiments. [Berglund et al., Sci. Immunol. 5, eabb5077 (2020)]
Interestingly, in MS, cells called microglia demonstrate an increased pro-inflammatory profile with both age and disease burden, the authors continued. “The capacity of microglia to clear tissue debris is essential for maintaining and restoring CNS homeostasis. This capacity diminishes with age, and age strongly associates with MS disease progression, although the underlying mechanisms are still largely elusive.”

In previous work, Berglund and colleagues had established a link between debris clearance in the CNS and disease severity in mice with experimental autoimmune encephalomyelitis (EAE), a common model of MS. The newly reported research in EAE mice found that recovery from brain inflammation depended on microglia performing debris-clearing functions in the CNS. The team’s studies showed that deleting a non-canonical autophagy gene Atg7 in the microglia of EAE mice led to accumulation of dead cell debris and propelled progressive MS-like disease. “Microglia-specific deletion of the autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin and progressive MS-like disease,” the investigators wrote.

Clec7a expression characterizes a microglia population associated with neurodegenerative conditions. Mice lacking Atg7 expression (bottom row) showed a markedly increased number of CLEC7A-expressing microglia (red and indicated by arrows in last column) compared with control mice (top row). [Berglund et al., Sci. Immunol. 5, eabb5077 (2020)]
Interestingly, Atg7-deficient microglia showed striking similarities to microglia from normal, aged mice that were also unable to clear debris or control disease. “Moreover, Atg7-deficient microglia showed notable transcriptional and functional similarities to microglia from aged wild-type mice that were also unable to clear myelin and recover from disease,” the team continued.

Conversely, triggering microglial cleaning functions in mice by giving the animals the disaccharide trehalose helped lead to disease remission, suggesting that the sugar should be further investigated for its therapeutic potential. “We herein demonstrate that a noncanonical form of autophagy in microglia is responsible for myelin degradation and clearance and that impairment of this pathway, which occurs during aging, contributes to the progression of MS-like disease,” the team concluded. “We show that we can modulate this process therapeutically, with implications in other age-related neuroinflammatory diseases.”

“The plant and fungi-derived sugar trehalose restores the functional breakdown of myelin residues, stops the progression, and leads to recovery from MS-like disease,” said Berglund. “By enhancing this process we hope one day to be able to treat and prevent age-related aspects of neuroinflammatory conditions.”

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