Innate immune training restores pro-reparative myeloid functions to promote remyelination in the aged central nervous system.

The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming.

Myelin dysfunction drives amyloid-ß deposition in models of Alzheimer's disease.

The incidence of Alzheimer's disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths1, the latter of which is associated with secondary neuroinflammation2,3. As oligodendrocytes support axonal energy metabolism and neuronal health4-7, we hypothesized that loss of myelin integrity could be an upstream risk factor for neuronal amyloid-ß (Aß) deposition, the central neuropathological hallmark of AD. Here we identify genetic pathways of myelin dysfunction and demyelinating injuries as potent drivers of amyloid deposition in mouse models of AD. Mechanistically, myelin dysfunction causes the accumulation of the Aß-producing machinery within axonal swellings and increases the cleavage of cortical amyloid precursor protein. Suprisingly, AD mice with dysfunctional myelin lack plaque-corralling microglia despite an overall increase in their numbers. Bulk and single-cell transcriptomics of AD mouse models with myelin defects show that there is a concomitant induction of highly similar but distinct disease-associated microglia signatures specific to myelin damage and amyloid plaques, respectively. Despite successful induction, amyloid disease-associated microglia (DAM) that usually clear amyloid plaques are apparently distracted to nearby myelin damage. Our data suggest a working model whereby age-dependent structural defects of myelin promote Aß plaque formation directly and indirectly and are therefore an upstream AD risk factor. Improving oligodendrocyte health and myelin integrity could be a promising target to delay development and slow progression of AD.

A fluorescence microscopy-based protocol for volumetric measurement of lysolecithin lesion-associated de- and re-myelination in mouse brain.

Lysolecithin injections into the white matter tracts of the central nervous system are a valuable tool to study remyelination, but evaluating the resulting demyelinating lesion size is challenging. Here, we present a protocol to consistently measure the volume of demyelination and remyelination in mice following brain lysolecithin injections. We describe serial sectioning of the lesion, followed by the evaluation of the demyelinated area in two-dimensional images. We then detail the computation of the volume using our own automated iPython script. For complete details on the use and execution of this profile, please refer to Bosch-Queralt et al. (2021).

Diet-dependent regulation of TGFß impairs reparative innate immune responses after demyelination.

Proregenerative responses are required for the restoration of nervous-system functionality in demyelinating diseases such as multiple sclerosis (MS). Yet, the limiting factors responsible for poor CNS repair are only partially understood. Here, we test the impact of a Western diet (WD) on phagocyte function in a mouse model of demyelinating injury that requires microglial innate immune function for a regenerative response to occur. We find that WD feeding triggers an ageing-related, dysfunctional metabolic response that is associated with impaired myelin-debris clearance in microglia, thereby impairing lesion recovery after demyelination. Mechanistically, we detect enhanced transforming growth factor beta (TGFß) signalling, which suppresses the activation of the liver X receptor (LXR)-regulated genes involved in cholesterol efflux, thereby inhibiting phagocytic clearance of myelin and cholesterol. Blocking TGFß or promoting triggering receptor expressed on myeloid cells 2 (TREM2) activity restores microglia responsiveness and myelin-debris clearance after demyelinating injury. Thus, we have identified a druggable microglial immune checkpoint mechanism regulating the microglial response to injury that promotes remyelination.