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Review
. 2019 Nov 7;10:1168.
doi: 10.3389/fneur.2019.01168. eCollection 2019.

Mitochondrial Cholesterol in Alzheimer's Disease and Niemann-Pick Type C Disease

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Free PMC article
Review

Mitochondrial Cholesterol in Alzheimer's Disease and Niemann-Pick Type C Disease

Sandra Torres et al. Front Neurol. .
Free PMC article

Abstract

Mitochondrial dysfunction has been recognized as a key player in neurodegenerative diseases, including Alzheimer's disease (AD) and Niemann-Pick type C (NPC) disease. While the pathogenesis of both diseases is different, disruption of intracellular cholesterol trafficking has emerged as a common feature of both AD and NPC disease. Nutritional or genetic mitochondrial cholesterol accumulation sensitizes neurons to Aβ-mediated neurotoxicity in vitro and promotes cognitive decline in AD models. In addition to the primary accumulation of cholesterol and sphingolipids in lysosomes, NPC disease is also characterized by an increase in mitochondrial cholesterol levels in affected organs, predominantly in brain and liver. In both diseases, mitochondrial cholesterol accumulation disrupts membrane physical properties and restricts the transport of glutathione into mitochondrial matrix, thus impairing the mitochondrial antioxidant defense strategy. The underlying mechanisms leading to mitochondrial cholesterol accumulation in AD and NPC diseases are not fully understood. In the present manuscript, we discuss evidence for the potential role of StARD1 in promoting the trafficking of cholesterol to mitochondria in AD and NPC, whose upregulation involves an endoplasmic reticulum stress and a decrease in acid ceramidase expression, respectively. These findings imply that targeting StARD1 or boosting the mitochondrial antioxidant defense may emerge as a promising approach for both AD and NPC disease.

Keywords: acid ceramidase; cholesterol; lysosomal disorders; mitochondria; sphingolipids.

Figures

Figure 1
Figure 1
Schematic representation of the putative mechanisms of StARD1 upregulation in AD and NPC. Mitochondrial cholesterol accumulation and subsequent mGSH depletion is a common feature of AD and NPC and its correlates with increased expression of StARD1. Since StARD1 is critical for mitochondrial cholesterol trafficking, it is conceivable that StARD1 is located in the MAM interface between ER and mitochondria. While in AD, ER stress by Aβ may contribute to StARD1 upregulation, this event does not seem to play a role in NPC. Given the repression of StARD1 by ACDase, we propose that ACDase downregulation may contribute to StARD1 induction in NPC disease, which requires further investigation. In both diseases, mitochondrial cholesterol accumulation disrupts membrane physical properties and impairs the transport of GSH into mitochondria, via the 2-oxoglutarate carrier (OGC), disrupting the mitochondrial antioxidant defense and subsequent oxidative stress. Chol, cholesterol; mGSH, mitochondrial glutathione; ROS, reactive oxygen species.

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