Abstract
Glucocerebrosidase (GCase) functions as a lysosomal enzyme and its mutations are known to be related to many neurodegenerative diseases, including Gaucher’s disease (GD), Parkinson’s disease (PD), and Dementia with Lewy Bodies (DLB). However, there is little information about the role of GCase in the pathogenesis of Alzheimer’s disease (AD). Here we demonstrate that GCase protein levels and enzyme activity are significantly decreased in sporadic AD. Moreover, Aβ1–42 oligomer treatment results in neuronal cell death that is concomitant with decreased GCase protein levels and enzyme activity, as well as impairment in lysosomal biogenesis and acidification. Importantly, overexpression of GCase promotes the lysosomal degradation of Aβ1–42 oligomers, restores the lysosomal impairment, and protects against the toxicity in neurons treated with Aβ1–42 oligomers. Our findings indicate that a deficiency of GCase could be involved in progression of AD pathology and suggest that augmentation of GCase activity may be a potential therapeutic option for the treatment of AD.
Highlights
The abnormal deposition of aggregated proteins such as amyloid-β (Aβ), tau, α-synuclein, and TAR DNA-binding protein (TDP-43) are linked to various age-related neurodegenerative disorders [1, 2]
GCase protein levels and enzyme activity are decreased in sporadic Alzheimer’s disease (AD) and Aβ1–42 oligomer-treated neurons
Despite the growing evidence implicating GCase in neurodegenerative disorders such as Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB), and Gaucher’s disease (GD), very little research has explored the relationship of GCase protein levels and enzyme activity to AD pathology except for the finding from Xu and colleagues suggesting that aggregates of Aβ and amyloid precursor protein (APP) are increased in GD mice, raising the possibility that GCase deficiency contributes to AD [41]
Summary
The abnormal deposition of aggregated proteins such as amyloid-β (Aβ), tau, α-synuclein, and TAR DNA-binding protein (TDP-43) are linked to various age-related neurodegenerative disorders [1, 2]. Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, the pathological hallmark of which is the accumulation of oligomeric Aβ peptides and PLOS ONE | DOI:10.1371/journal.pone.0143854 December 2, 2015
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