Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function

Area of Science:

• Neuroscience
• Biochemistry
• Ophthalmology

Background:

• Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, encoding acid sphingomyelinase (aSMase), cause Niemann-Pick disease (NPD) types A and B.
• Sphingomyelin accumulation in the mononuclear phagocyte system leads to hepatosplenomegaly and severe neurodegeneration in NPD patients.
• The specific impact of aSMase deficiency on retinal structure and microglial behavior remains largely uncharacterized.

Purpose of the Study:

• To investigate the effects of aSMase deficiency on retinal structure and function in a mouse model.
• To examine microglial behavior and lipid accumulation in the retinas of aSMase-deficient mice.

Main Methods:

• Utilized aSMase(-/-) mice to model Niemann-Pick disease.
• Performed electroretinography to assess retinal function (scotopic and photopic responses).
• Employed in vivo fundus imaging, Iba1 staining for microglia, Nile red staining for lipid inclusions, and lipid analysis.

Main Results:

• aSMase(-/-) mouse retinas showed no overt neuronal degeneration but exhibited significantly reduced scotopic and photopic responses.
• Fundus imaging revealed hyperreflective spots, and Iba1 staining indicated massive microglial proliferation with enlarged cell bodies.
• Nile red staining identified prominent phospholipid inclusions in microglia, and lipid analysis confirmed increased sphingomyelin levels in the retinas.

Conclusions:

• The aSMase-deficient mouse model demonstrates significant microglial lipid inclusions and associated retinal dysfunction.
• This study establishes a direct relationship between microglial lipid accumulation and loss of retinal function in the absence of neuronal degeneration.
• The findings highlight a novel aspect of Niemann-Pick disease pathology affecting the retina through microglial alterations.