Progressive retinal degeneration and glial activation in the CLN6 (nclf) mouse model of neuronal ceroid lipofuscinosis: a beneficial effect of DHA and curcumin supplementation

PLoS One. 2013 Oct 4;8(10):e75963. doi: 10.1371/journal.pone.0075963. eCollection 2013.

Abstract

Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by vision loss, mental and motor deficits, and spontaneous seizures. Neuropathological analyses of autopsy material from NCL patients and animal models revealed brain atrophy closely associated with glial activity. Earlier reports also noticed loss of retinal cells and reactive gliosis in some forms of NCL. To study this phenomenon in detail, we analyzed the ocular phenotype of CLN6 (nclf) mice, an established mouse model for variant-late infantile NCL. Retinal morphometry, immunohistochemistry, optokinetic tracking, electroretinography, and mRNA expression were used to characterize retinal morphology and function as well as the responses of Müller cells and microglia. Our histological data showed a severe and progressive degeneration in the CLN6 (nclf) retina co-inciding with reactive Müller glia. Furthermore, a prominent phenotypic transformation of ramified microglia to phagocytic, bloated, and mislocalized microglial cells was identified in CLN6 (nclf) retinas. These events overlapped with a rapid loss of visual perception and retinal function. Based on the strong microglia reactivity we hypothesized that dietary supplementation with immuno-regulatory compounds, curcumin and docosahexaenoic acid (DHA), could ameliorate microgliosis and reduce retinal degeneration. Our analyses showed that treatment of three-week-old CLN6 (nclf) mice with either 5% DHA or 0.6% curcumin for 30 weeks resulted in a reduced number of amoeboid reactive microglia and partially improved retinal function. DHA-treatment also improved the morphology of CLN6 (nclf) retinas with a preserved thickness of the photoreceptor layer in most regions of the retina. Our results suggest that microglial reactivity closely accompanies disease progression in the CLN6 (nclf) retina and both processes can be attenuated with dietary supplemented immuno-modulating compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Curcumin / therapeutic use*
  • Disease Models, Animal
  • Docosahexaenoic Acids / therapeutic use*
  • Mice
  • Neuronal Ceroid-Lipofuscinoses / drug therapy*
  • Neuronal Ceroid-Lipofuscinoses / genetics
  • Neuronal Ceroid-Lipofuscinoses / metabolism
  • Retina / drug effects
  • Retina / pathology

Substances

  • Docosahexaenoic Acids
  • Curcumin

Supplementary concepts

  • Ceroid Lipofuscinosis, Neuronal, 6

Grant support

This study was supported by the NCL foundation, the Auerbach foundation, the NCL group Germany, the Stock foundation, and the DFG (LA1203/6-2 and 8-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.