Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann–Pick type C1 mice

Sarah N.R Pressey,David A Smith,Andrew M.S Wong,Frances M Platt,Jonathan D Cooper

doi:10.1016/j.nbd.2011.12.027

Sarah N.R Pressey, David A Smith + Show 3 more

Open Access

https://doi.org/10.1016/j.nbd.2011.12.027

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Abstract

Niemann–Pick disease type C (NPC) is an inherited lysosomal storage disease characterised by accumulation of cholesterol and glycosphingolipids. NPC patients suffer a progressive neurodegenerative phenotype presenting with motor dysfunction, mental retardation and cognitive decline. To examine the onset and progression of neuropathological insults in NPC we have systematically examined the CNS of a mouse model of NPC1 (Npc1−/− mice) at different stages of the disease course. This revealed a specific spatial and temporal pattern of neuropathology in Npc1−/− mice, highlighting that sensory thalamic pathways are particularly vulnerable to loss of NPC1 resulting in neurodegeneration in Npc1−/− mice. Examination of markers of astrocytosis and microglial activation revealed a particularly pronounced reactive gliosis in the thalamus early in the disease, which subsequently also occurred in interconnected cortical laminae at later ages. Our examination of the precise staging of events demonstrate that the relationship between glia and neurons varies between brain regions in Npc1−/− mice, suggesting that the cues causing glial reactivity may differ between brain regions. In addition, aggregations of pre-synaptic markers are apparent in white matter tracts and the thalamus and are likely to be formed within axonal spheroids. Our data provide a new perspective, revealing a number of events that occur prior to and alongside neuron loss and highlighting that these occur in a pathway dependent manner.

Highlights

Niemann–Pick type C (NPC) is one of more than 50 inherited lysosomal storage disorders (LSDs), and like many of these disorders, is characterised by progressive neurological decline (Brady et al, 1966; Crocker and Farber, 1958)
The severe neurological phenotypes displayed by Npc1−/− mice are accompanied by marked changes in both neurons and glia (Baudry et al, 2003; German et al, 2002; Suzuki et al, 2003), but the onset and progression of these events have not been characterised in detail
To further understand the time course of neuropathological changes in Npc1−/− mice we have systematically examined the forebrain of Npc1−/− mice at different stages of disease progression

Summary

Introduction

Niemann–Pick type C (NPC) is one of more than 50 inherited lysosomal storage disorders (LSDs), and like many of these disorders, is characterised by progressive neurological decline (Brady et al, 1966; Crocker and Farber, 1958). Neurological signs include ataxia, mental retardation, tremors, vertical supranuclear gaze palsy and dementia (Garver et al, 2007; Vanier, 2010). This disease can present neonatally, in childhood, adolescence or during adulthood resulting. A plethora of lipids accumulate in NPC disease including neutral glycosphingolipids, gangliosides, sphingomyelin and sphingosine (Vanier, 1999). In the brain, which is the major site of NPC disease pathology, there is significant accumulation of gangliosides and sphingolipids (Siegel and Walkley, 1994; Vanier, 1999; Zervas et al, 2001). There is currently no consensus on what the functional role of the NPC disease pathway is and which metabolite is the central player in pathogenesis (Lloyd-Evans and Platt, 2010)

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