ASM in Alzheimer's disease

A remarkable rise in life expectancy and the declining prevalence of certain causes of late-life mortality allow dementia to become a common occurrence with age. Alzheimer's disease (AD) is the most prevalent form of dementia characterized clinically by progressive loss of memory, and pathologically by the presence of neuritic plaques and neurofibrillary tangles [1]. Many scientists effort to understand the AD pathogenesis by investigating a complex interaction between genes and the environment. There are profound biochemical alterations in multiple pathways in the AD brain, including changes in amyloid-β (Aβ) metabolism, tau phosphorylation, lipid regulation, and cellular disposal system, although to date the underlying mechanism(s) leading to these complex abnormalities, remain largely unknown [1-3]. Acid sphingomyelinase (ASM, EC 3.1.4.12) is a key enzyme that regulates tissue homeostasis by affecting diverse signaling process, including cell survival, proliferation, and differentiation, but also in senescence and apoptosis [2, 4]. In the brain, this enzyme normally works in harmony with other sphingolipid-metabolizing enzymes and sphingolipid metabolites for proper neuronal function. Therefore, the subtle changes in sphingolipid homeostasis by ASM are intimately involved in neurodegenerative diseases including AD [4]. However, the role of ASM in AD and the cellular mechanisms that link ASM and AD have not been fully characterized. In a recent study published in Journal of Experimental Medicine, we reported that increased ASM activity in AD results in defective autophagy due to disruption of lysosomal biogenesis [5]. ASM activity was significantly increased in plasma and fibroblast samples derived from AD patients compared with that of normal aged individuals [5]. ASM was not elevated in samples from Parkinson's disease patients. These results confirmed ASM activity is a specific signature of AD and influence disease progression and/or pathogenesis. To address the influence of ASM on AD pathology, amyloid precursor protein/presenilin 1 (APP/PS1) double mutant and APP/ PS1/ASM +/-triple mutant mice were used. Similar to AD patients, ASM activity was elevated in plasma, fibroblast, and brain (especially neurons) of APP/PS1 mice. This activity was decreased in APP/PS1/ASM +/-mice to levels within the normal range or lower. Strikingly, AD pathology including Aβ deposition and memory dysfunction was significantly reduced in APP/PS1/ASM +/-mice [5]. There is growing evidence to suggest that dysfunction of the proteolytic degradation system could affect AD pathogenesis and lead to enhanced Aβ deposition. Autophagy, a process to destroy misfolded proteins or breakdown faulty components and then recycle, is known to be markedly impaired in AD …