Focal white matter lesions drive grey matter inflammation and synapse loss | Nature

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Subjects

- Alzheimer's disease

- Multiple sclerosis

- Neuroimmunology

Abstract

Focal white matter lesions occur in most neurodegenerative disorders1,2,3. Despite occurring early in disease, white matter lesions are considered to be independent of, or secondary to, grey matter neuroinflammation, synapse loss and altered neuronal activity4,5,6,7. Notably, their functional effect on neuronal circuits remains understudied. To address this, we generated a focal white matter lesion in the rat brain within a clinically relevant, anatomically well-defined circuit, in which these lesions occur in many neurodegenerative disorders8,9,10. Here we show that focal white matter lesions evoke transient neuronal activity changes and microgliosis, with subsequent synapse loss and increased microglial engulfment in the grey matter, which is reversed if myelin regeneration completes. Grey matter microgliosis is often considered to be detrimental; however, we show that it is an integral part of regeneration and is conserved across three distinct mouse circuits and lesioning methods. Preventing these transient changes in the grey matter blocks myelin regeneration in the white matter. Conversely, inducing myelin regeneration failure leads to chronic grey matter neuroinflammation. This recapitulates the low-grade inflammation considered to be a dominant mechanism underlying neurodegeneration7,11,12. Our findings reveal a form of regenerative plasticity coupling white matter integrity to grey matter function, which may underlie multiple neurodegenerative conditions, and highlight the potential of targeting myelin regeneration to prevent chronic neuroinflammation.

Main

Focal white matter lesions accumulate with age in the central nervous system (CNS) and, in neurodegenerative conditions, their number correlates with cognitive and physical impairment1,2,3,13. Multiple sclerosis (MS) is a demyelinating disorder characterized by white matter demyelinating lesions1,7. Grey matter microgliosis, and synaptic and neuronal functional loss, also occur; however, they are considered independent of lesions and lead to irreversible neurodegeneration, thought to be the dominant mechanism underlying disability progression5,7. Neurodegeneration in MS is characterized by low-grade inflammation and ineffective myelin regeneration7,14. This is common in other neurodegenerative conditions, such as dementia, Alzheimer’s disease and Parkinson’s disease1,2,3,4, in which white matter lesions occur early in disease but have been traditionally considered secondary to neuronal loss. However, recent evidence indicates that dysfunctional myelin may affect microglial and neuronal function in mouse models of Alzheimer’s disease15,16,17.

Neurodegenerative disorders, including MS, result in considerable personal, societal and economic burdens, and there are currently no fully effective treatments preventing progression. Changes in neuronal activity6,18, microglial activation in the grey matter and synapse engulfment5,18 occur in models of diffuse demyelination, and synapse loss and microgliosis are also detected in postmortem tissues from people with MS5,7,19 and other neurodegenerative disorders11. The observed grey matter changes are often considered independent of the demyelinating injury5,6,18, potentially due to the anatomical separation, despite total brain volume loss and cognitive decline correlating with white matter lesion burden13,20. The effect of focal white matter lesions on neuronal function and grey matter inflammation remains unclear despite these lesions being a common hallmark of age-related neurodegenerative disorders.

To address this, we induced a focal white matter lesion in an anatomically well-defined circuit and found that it evoked transient and localized grey matter inflammation, synaptic loss and altered neuronal activity, that resolved after white matter regeneration. In contrast to current notions, we found that focal white matter lesions are not secondary to nor independent of, but instead are drivers of, neuronal dysfunction, synapse loss and grey matter inflammation. Rather than being detrimental, these transient effects are an integral part of the regenerative process, with failure leading to ongoing chronic inflammation. This reflects a form of neural plasticity that ensures neuronal health and supports regeneration through coordinated grey–white matter interactions, reframing our understanding of how the nervous system orchestrates regeneration.

Mapping the circuit after a focal white matter lesion

To investigate functional implications of focal white matter lesions for neuronal circuits, we chose the well-defined olivocerebellar circuit for its anatomical separation of afferent and efferent white matter tracts (Fig. 1a). White matter lesions occur in this circuit in MS and other neurodegenerative disorders, such as Alzheimer’s disease, dementia and Parkinson’s disease, and correlate with executive a