Progressive Retinal Degeneration and Glial Activation in the CLN6nclf Mouse Model of Neuronal Ceroid Lipofuscinosis: A Beneficial Effect of DHA and Curcumin Supplementation

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 CLN6nclf 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 CLN6nclf 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 CLN6nclf 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 CLN6nclf 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 CLN6nclf 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 CLN6nclf retina and both processes can be attenuated with dietary supplemented immuno-modulating compounds.

Mutations in MFSD8, Encoding a Lysosomal Membrane Protein, Are Associated with Nonsyndromic Autosomal Recessive Macular Dystrophy

“…Moreover, intake of docosahexaenoic acid also improved the retinal morphology by preservation of the photoreceptor layer thickness. 59 Our hypothesis that nonsyndromic retinal degeneration is caused by relatively mild MFSD8 deficiencies could imply that only a minor increase of protein function, or suppression of Müller cell activation, might result in a significant therapeutic effect.…”

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

“…Longer-term studies will be needed to investigate the safety and effectiveness of these approaches. Other proposed treatments, including substrate reduction and use of anti-inflammatory reagents, can contribute to mitigating aspects of MPS pathology [12,52,71]. Because of its exceptionally good toxicological profile [72,73], trehalose might be safely used in combination therapies to investigate its additive or synergistic effects with other therapeutics.…”

Curcumin boosts DHA in the brain: Implications for the prevention of anxiety disorders

“…Turmeric is a household staple in India, with reported average daily consumption ranging from 0.24 g/person/day to as high as 4g/person/day [80, 81]. Curcumin, which is a naturally polyphenolic compound found in turmeric has multifaceted medicinal properties and has been implicated in helping to treat several types of neurological disorders including Alzheimer’s disease [39, 82, 83], retinal diseases [84, 85], Parkinson’s disease [86, 87], stroke [88], brain injury [22, 41, 42] and psychiatric disorders [89–91]. We recently reported that curcumin supplementation promoted increased DHA content in the brain following TBI, and that this effect was associated with elevated levels of enzymes involved in DHA synthesis [22].…”