Neutral or Detrimental Effects of TREM2 Agonist Antibodies in Preclinical Models of Alzheimer's Disease and Multiple Sclerosis.

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia.

TREM2-dependent microglial function is essential for remyelination and subsequent neuroprotection.

Disability in multiple sclerosis (MS) is driven in part by the failure of remyelination and progressive neurodegeneration. Microglia, and specifically triggering receptor expressed on myeloid cells 2 (TREM2), a factor highly expressed in microglia, have been shown to play an important role in remyelination. Here, using a focal demyelination model in the brain, we demonstrate that demyelination is persistent in TREM2 knockout mice, lasting more than 6 weeks after lysolecithin injection and resulting in substantial neurodegeneration.

Disease-associated oligodendrocyte responses across neurodegenerative diseases.

Oligodendrocyte dysfunction has been implicated in the pathogenesis of neurodegenerative diseases, so understanding oligodendrocyte activation states would shed light on disease processes. We identify three distinct activation states of oligodendrocytes from single-cell RNA sequencing (RNA-seq) of mouse models of Alzheimer's disease (AD) and multiple sclerosis (MS): DA1 (disease-associated1, associated with immunogenic genes), DA2 (disease-associated2, associated with genes influencing survival), and IFN (associated with interferon response genes). Spatial analysis of disease-associated oligodendrocytes (DAOs) in the cuprizone model reveals that DA1 and DA2 are established outside of the lesion area during demyelination and that DA1 repopulates the lesion during remyelination.

Multiple sclerosis risk gene Mertk is required for microglial activation and subsequent remyelination.

In multiple sclerosis (MS) and other neurological diseases, the failure to repair demyelinated lesions contributes to axonal damage and clinical disability. Here, we provide evidence that Mertk, a gene highly expressed by microglia that alters MS risk, is required for efficient remyelination. Compared to wild-type (WT) mice, Mertk-knockout (KO) mice show impaired clearance of myelin debris and remyelination following demyelination.

Selective Estrogen Receptor Modulators Enhance CNS Remyelination Independent of Estrogen Receptors.

A significant unmet need for patients with multiple sclerosis (MS) is the lack of U.S. Food and Drug Administration (FDA)-approved remyelinating therapies.

Initiation of CNS Myelination in the Optic Nerve Is Dependent on Axon Caliber.

Emerging evidence suggests that neuronal signaling is important for oligodendrocyte myelination; however, the necessity of this signaling during development is unclear. By eliminating dynamic neuronal signaling along the developing optic nerve, we find that oligodendrocyte differentiation is not dependent on neuronal signaling and that the initiation of myelination is dependent on a permissive substrate, namely supra-threshold axon caliber. Furthermore, we show that loss of dynamic neuronal signaling results in hypermyelination of axons.

Modeling CNS Myelination Using Micropillar Arrays.

Myelination necessitates axons to initiate concentric membrane wrapping by oligodendroglia in the CNS. Here, we describe an in vitro system that models CNS myelination with a minimally permissive environment, termed Binary Indicant for myelination using Micropillar Arrays (BIMA). Engineered with conical micropillar arrays, BIMA allows for rapid translation of oligodendroglial wrapping and differentiation into binary readout under confocal microscopy.

Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury.

Hypoxia can injure brain white matter tracts, comprised of axons and myelinating oligodendrocytes, leading to cerebral palsy in neonates and delayed post-hypoxic leukoencephalopathy (DPHL) in adults. In these conditions, white matter injury can be followed by myelin regeneration, but myelination often fails and is a significant contributor to fixed demyelinated lesions, with ensuing permanent neurological injury. Non-myelinating oligodendrocyte precursor cells are often found in lesions in plentiful numbers, but fail to mature, suggesting oligodendrocyte precursor cell differentiation arrest as a critical contributor to failed myelination in hypoxia.

Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery.

Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination.

Somatodendritic Expression of JAM2 Inhibits Oligodendrocyte Myelination.

Myelination occurs selectively around neuronal axons to increase the efficiency and velocity of action potentials. While oligodendrocytes are capable of myelinating permissive structures in the absence of molecular cues, structurally permissive neuronal somata and dendrites remain unmyelinated. Utilizing a purified spinal cord neuron-oligodendrocyte myelinating co-culture system, we demonstrate that disruption of dynamic neuron-oligodendrocyte signaling by chemical cross-linking results in aberrant myelination of the somatodendritic compartment of neurons.

Phosphorylation of LKB1/Par-4 establishes Schwann cell polarity to initiate and control myelin extent.

The Schwann cell (SC)-axon interface represents a membrane specialization that integrates axonal signals to coordinate cytoskeletal dynamics resulting in myelination. Here we show that LKB1/Par-4 is asymmetrically localized to the SC-axon interface and co-localizes with the polarity protein Par-3. Using purified SCs and myelinating cocultures, we demonstrate that localization is dependent on the phosphorylation of LKB1 at serine-431.

Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis.

Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats.

Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination.

A requisite component of nervous system development is the achievement of cellular recognition and spatial segregation through competition-based refinement mechanisms. Competition for available axon space by myelinating oligodendrocytes ensures that all relevant CNS axons are myelinated properly. To ascertain the nature of this competition, we generated a transgenic mouse with sparsely labeled oligodendrocytes and establish that individual oligodendrocytes occupying similar axon tracts can greatly vary the number and lengths of their myelin internodes.

Assessing the role of the cadherin/catenin complex at the Schwann cell-axon interface and in the initiation of myelination.

Myelination is dependent on complex reciprocal interactions between the Schwann cell (SC) and axon. Recent evidence suggests that the SC-axon interface represents a membrane specialization essential for myelination; however, the manner in which this polarized-apical domain is generated remains a mystery. The cell adhesion molecule N-cadherin is enriched at the SC-axon interface and colocalizes with the polarity protein Par-3.