Combined Treatment of Ketogenic Diet and Propagermanium Reduces Neuroinflammation in Tay-Sachs Disease Mouse Model

Abstract

Abstract Tay-Sachs disease is a rare lysosomal storage disorder caused by β-hexosaminidase A enzyme deficiency causing abnormal GM2 ganglioside accumulation in the central nervous system. GM2 accumulation triggers chronic neuroinflammation due to neurodegeneration-based astrogliosis and macrophage activity with the increased expression level of Ccl2 in the cortex of a recently generated Tay-Sachs disease mouse model Hexa-/-Neu3-/-. Propagermanium blocks the neuroinflammatory response induced by Ccl2, which is highly expressed in astrocytes and microglia. The ketogenic diet has broad potential usage in neurological disorders, but the knowledge of the impact on Tay-Sach disease is limited. This study aimed to display the effect of combining the ketogenic diet and propagermanium treatment on chronic neuroinflammation in the Tay-Sachs disease mouse model. Hexa-/-Neu3-/- mice were placed into the following groups: (i) chow diet, (ii) ketogenic diet (iii) chow diet with propagermanium, and (iv) ketogenic diet with propagermanium. Neuroinflammation markers were analyzed by RT-PCR and immunohistochemistry. Behavioral analyses were also applied for the assessment of phenotypic improvement. Notably,the expression levels of neuroinflammation-related genes were reduced in the cortex of 140-day-old Hexa-/-Neu3-/- mice compared to β-hexosaminidase A deficient mice Hexa-/- after combined treatment. Immunohistochemical analysis displayed correlated results with the RT-PCR. Our data suggest the potential to implement combined treatment to reduce chronic inflammation in Tay-Sachs and other lysosomal storage diseases.