White matter aging and its impact on brain function.

Aging has a detrimental impact on white matter, resulting in reduced volume, compromised structural integrity of myelinated axons, and an increase in white matter hyperintensities. These changes are closely linked to cognitive decline and neurological disabilities. The deterioration of myelin and its diminished ability to regenerate as we age further contribute to the progression of neurodegenerative disorders.

Loss of CLN3 in microglia leads to impaired lipid metabolism and myelin turnover.

Loss-of-function mutations in CLN3 cause juvenile Batten disease, featuring neurodegeneration and early-stage neuroinflammation. How loss of CLN3 function leads to early neuroinflammation is not yet understood. Here, we have comprehensively studied microglia from Cln3 mice, a genetically accurate disease model.

Clinically approved immunomodulators ameliorate behavioral changes in a mouse model of hereditary spastic paraplegia type 11.

We have previously demonstrated that neuroinflammation by the adaptive immune system acts as a robust and targetable disease amplifier in a mouse model of Spastic Paraplegia, type 11 (SPG11), a complicated form of Hereditary Spastic Paraplegia (HSP). While we identified an impact of neuroinflammation on distinct neuropathological changes and gait performance, neuropsychological features, typical and clinically highly relevant symptoms of complicated HSPs, were not addressed. Here we show that the corresponding SPG11 mouse model shows distinct behavioral abnormalities, particularly related to social behavior thus partially reflecting the neuropsychological changes in patients.

Brain-to-gut trafficking of alpha-synuclein by CD11c cells in a mouse model of Parkinson's disease.

Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson's disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics.

Microglia-mediated demyelination protects against CD8 T cell-driven axon degeneration in mice carrying PLP defects.

Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes.

Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed oligodendrocytes in mutant mice.

Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct mutations result in neurodegeneration that is largely driven by adaptive immune cells.

Teriflunomide as a therapeutic means for myelin repair.

Background: Promotion of myelin repair in the context of demyelinating diseases such as multiple sclerosis (MS) still represents a clinical unmet need, given that this disease is not only characterized by autoimmune activities but also by impaired regeneration processes. Hence, this relates to replacement of lost oligodendrocytes and myelin sheaths-the primary targets of autoimmune attacks. Endogenous remyelination is mainly mediated via activation and differentiation of resident oligodendroglial precursor cells (OPCs), whereas its efficiency remains limited and declines with disease progression and aging.

CD8 T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging.

A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found age-related alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8 T cells in aging white matter.

CNS-associated T-lymphocytes in a mouse model of Hereditary Spastic Paraplegia type 11 (SPG11) are therapeutic targets for established immunomodulators.

Pharmacological targeting of neuroinflammation in distinct models of genetically mediated disorders of the central nervous system (CNS) has been shown to attenuate disease outcome significantly. These include mouse models mimicking distinct subtypes of neuronal ceroid lipofuscinoses (NCL, CLN diseases) as well as hereditary spastic paraplegia type 2 (HSP/SPG2). We here show in a model of another, complicated HSP form (SPG11) that there is neuroinflammation in distinct compartments of the diseased CNS.

Early targeting of endoneurial macrophages alleviates the neuropathy and affects abnormal Schwann cell differentiation in a mouse model of Charcot-Marie-Tooth 1A.

We have previously shown that targeting endoneurial macrophages with the orally applied CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 from the age of 3 months onwards led to a substantial alleviation of the neuropathy in mouse models of Charcot-Marie-Tooth (CMT) 1X and 1B disease, which are genetically-mediated nerve disorders not treatable in humans. The same approach failed in a model of CMT1A (PMP22-overexpressing mice, line C61), representing the most frequent form of CMT. This was unexpected since previous studies identified macrophages contributing to disease severity in the same CMT1A model.

Immune modulation attenuates infantile neuronal ceroid lipofuscinosis in mice before and after disease onset.

Targeting neuroinflammation in models for infantile and juvenile forms of neuronal ceroid lipofuscinosis (NCL, CLN disease) with the clinically established immunomodulators fingolimod and teriflunomide significantly attenuates the neurodegenerative phenotype when applied preventively, i.e. before the development of substantial neural damage and clinical symptoms.

Accumulation of cytotoxic T cells in the aged CNS leads to axon degeneration and contributes to cognitive and motor decline.

Aging is a major risk factor for the development of nervous system functional decline, even in the absence of diseases or trauma. The axon-myelin units and synaptic terminals are some of the neural structures most vulnerable to aging-related deterioration, but the underlying mechanisms are poorly understood. In the peripheral nervous system, macrophages-important representatives of the innate immune system-are prominent drivers of structural and functional decline of myelinated fibers and motor endplates during aging.

Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice.

Background: The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice.

Secretome Analysis of Mesenchymal Stem Cell Factors Fostering Oligodendroglial Differentiation of Neural Stem Cells In Vivo.

Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far.

The CLN3 gene and protein: What we know.

Background: One of the most important steps taken by Beyond Batten Disease Foundation in our quest to cure juvenile Batten (CLN3) disease is to understand the State of the Science. We believe that a strong understanding of where we are in our experimental understanding of the CLN3 gene, its regulation, gene product, protein structure, tissue distribution, biomarker use, and pathological responses to its deficiency, lays the groundwork for determining therapeutic action plans.

Objectives: To present an unbiased comprehensive reference tool of the experimental understanding of the CLN3 gene and gene product of the same name.

Targeting microglia attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations.

Genetically caused neurological disorders of the central nervous system (CNS) usually result in poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with disease-amplifying neuroinflammation, a feature shared by progressive forms of multiple sclerosis (PMS), another poorly treatable disorder of the CNS. We have previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients fulfilling clinical criteria for multiple sclerosis (MS).

Teriflunomide attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations.

Background: Genetically caused neurological disorders of the central nervous system (CNS) are mostly characterized by poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with low-grade, disease-promoting inflammation, another feature shared by progressive forms of multiple sclerosis (PMS). We previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients diagnosed with MS.

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment.

Genetically caused neurological disorders of the central nervous system (CNS) are usually orphan diseases with poor or even fatal clinical outcome and few or no treatments that will improve longevity or at least quality of life. Neuroinflammation is common to many of these disorders, despite the fact that a plethora of distinct mutations and molecular changes underlie the disorders. In this article, data from corresponding animal models are analyzed to define the roles of innate and adaptive inflammation as modifiers and amplifiers of disease.

Fingolimod and Teriflunomide Attenuate Neurodegeneration in Mouse Models of Neuronal Ceroid Lipofuscinosis.

CLN diseases are rare lysosomal storage diseases characterized by progressive axonal degeneration and neuron loss in the CNS, manifesting in disability, blindness, and premature death. We have previously demonstrated that, in animal models of infantile and juvenile forms of CLN disease (CLN1 and CLN3, respectively), secondary neuroinflammation in the CNS substantially amplifies neural damage, opening the possibility that immunomodulatory treatment might improve disease outcome. First, we recapitulated the inflammatory phenotype, originally seen in mice in autopsies of CLN patients.

Pathogenic inflammation in the CNS of mice carrying human PLP1 mutations.

Progressive forms of multiple sclerosis lead to chronic disability, substantial decline in quality of life and reduced longevity. It is often suggested that they occur independently of inflammation. Here we investigated the disease progression in mouse models carrying PLP1 point mutations previously found in patients displaying clinical features of multiple sclerosis.

Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury.

Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis.

Cell-Surface and Secreted Isoforms of CSF-1 Exert Opposing Roles in Macrophage-Mediated Neural Damage in Cx32-Deficient Mice.

Unlabelled: Previous studies in myelin-mutant mouse models of the inherited and incurable nerve disorder, Charcot-Marie-Tooth (CMT) neuropathy, have demonstrated that low-grade secondary inflammation implicating phagocytosing macrophages amplifies demyelination, Schwann cell dedifferentiation and perturbation of axons. The cytokine colony stimulating factor-1 (CSF-1) acts as an important regulator of these macrophage-related disease mechanisms, as genetic and pharmacologic approaches to block the CSF-1/CSF-1R signaling result in a significant alleviation of pathological alterations in mutant peripheral nerves. In mouse models of CMT1A and CMT1X, as well as in human biopsies, CSF-1 is predominantly expressed by endoneurial fibroblasts, which are closely associated with macrophages, suggesting local stimulatory mechanisms.

Sialoadhesin promotes neuroinflammation-related disease progression in two mouse models of CLN disease.

CLN diseases are mostly fatal lysosomal storage diseases that lead to neurodegeneration in the CNS. We have previously shown that CD8+ T-lymphocytes contribute to axonal perturbation and neuron loss in the CNS of Ppt1(-/-) mice, a model of CLN1 disease. We now investigated the role of the inflammation-related cell adhesion molecule sialoadhesin (Sn) in Ppt1(-/-) and Cln3(-/-) mice, a model of the most frequent form, CLN3 disease.