Abstract
BackgroundThe 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.MethodsWe applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry.ResultsWe show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1−/− mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS.ConclusionsOur results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.
Highlights
The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS
Microglia/macrophage depletion using PLX3397 reveals sex- and CNS region-specific bias in Ppt1−/− mice We recently showed that targeting microglia using longterm oral administration of the colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 depletes microglia without obvious neurological side effects and significantly attenuates neuroinflammation-related neural damage in the CNS of a genetic model displaying features characteristic of progressive multiple sclerosis and hereditary spastic paraplegia [23, 24]
We here used the same approach to deplete microglia/macrophages in the CNS of Ppt1−/− mice
Summary
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). Neuronal ceroid lipofuscinosis (CLN) diseases are a group of rare inherited lysosomal storage diseases characterized by substantial neural damage in the CNS, culminating in neuron loss, mental and physical disability, and eventually leading to an early death [6, 41]. The CLNs are histopathologically characterized by the accumulation of lipofuscin-like autofluorescent storage material (ceroid) in most cell types of the CNS, neuroinflammation and neurodegeneration [56]. Mutations in the palmitoylprotein thioesterase 1 (PPT1), a soluble lysosomal enzyme, result in the devastating infantile form called CLN1 [34]
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