Abstract
Aging, which is associated with age-related changes in physiological processes, is the most significant risk factor for the development and progression of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Accumulating evidence has indicated that sphingolipids are significant regulators that are associated with pathogenesis in aging and several age-related neurodegenerative diseases. In particular, abnormal levels of acid sphingomyelinase (ASM), one of the significant sphingolipid-metabolizing enzymes, have been found in the blood and some tissues under various neuropathological conditions. Moreover, recent studies have reported the importance of ASM as a critical mediator that contributes to pathologies in aging and age-related neurodegenerative diseases. In this review, we describe the pathophysiological processes that are regulated by ASM, focusing on the age-related neurodegenerative environment. Furthermore, we discuss novel insights into how new therapeutics targeting ASM may potentially lead to effective strategies to combat aging and age-related neurodegenerative diseases.
Highlights
Aging, defined as the progressive decline in physiological function with time, is generally characterized by a reduced ability to cope with stress, failure to maintain homeostasis and increased risk of various diseases, including cancer, and cardiovascular and neurological diseases[1,2]
We focus on recent studies that describe the association between acid sphingomyelinase (ASM) and its involvement in aging and age-related neurodegenerative diseases
This study showed that inhibiting brain endothelial ASM activity improved these pathologies, suggesting that inhibition of brain endothelial ASM may be a highly valuable strategy for anti-aging. This result indicated that endothelial ASM mediates blood–brain barrier (BBB) dysfunction by increasing caveolae transcytosis in aged murine brains, future studies will need to address whether similar disruption of BBB integrity by endothelial ASM occurs in the aged human brains
Summary
In the CNS, these mediators are highly enriched in the brain, where they are pivotal components of cell membranes and play an essential role in proper brain development and function[23,24,25]. Microvessels derived from old murine brains exhibited significantly increased ERM dephosphorylation, which was improved by normalization of ASM activity[45] This suggests that EC-derived ASM increases caveolae internalization by cytoskeleton disruption through PP1mediated ERM dephosphorylation, leading to increased BBB permeability in the aged brain. This study showed that inhibiting brain endothelial ASM activity improved these pathologies, suggesting that inhibition of brain endothelial ASM may be a highly valuable strategy for anti-aging This result indicated that endothelial ASM mediates BBB dysfunction by increasing caveolae transcytosis in aged murine brains, future studies will need to address whether similar disruption of BBB integrity by endothelial ASM occurs in the aged human brains
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