Mucopolysaccharidosis type I (MPS I) is caused by genetic deficiency of α-l-
iduronidase and impairment of lysosomal catabolism of
heparan sulfate and
dermatan sulfate. In the brain, these substrates accumulate in the lysosomes of neurons and glial cells, leading to
neuroinflammation and neurodegeneration. Their storage also affects lysosomal homeostasis-inducing activity of several lysosomal
proteases including
cathepsin B (CATB). In the central nervous system, increased CATB activity has been associated with the deposition of
amyloid plaques due to an alternative pro-amyloidogenic processing of the
amyloid precursor
protein (APP), suggesting a potential role of this
enzyme in the neuropathology of MPS I. In this study, we report elevated levels of
protein expression and activity of CATB in cortex tissues of 6-month-old MPS I (Idua -/- mice. Besides, increased CATB leakage from lysosomes to the cytoplasm of Idua -/- cortical pyramidal neurons was indicative of damaged lysosomal membranes. The increased CATB activity coincided with an elevated level of the 16-kDa C-terminal APP fragment, which together with unchanged levels of β-
secretase 1 was suggestive for the role of this
enzyme in the amyloidogenic APP processing. Neuronal accumulation of
Thioflavin-S-positive misfolded
protein aggregates and drastically increased levels of neuroinflammatory
glial fibrillary acidic protein (GFAP)-positive astrocytes and CD11b-positive activated microglia were observed in Idua -/- cortex by confocal fluorescent microscopy. Together, our results point to the existence of a novel CATB-associated alternative amyloidogenic pathway in MPS I brain induced by lysosomal storage and potentially leading to neurodegeneration.