The blood-brain barrier is a lining of specialized cells that wraps all blood vessels passing through the central nervous system. It allows only certain molecules to pass, keeping the biochemistry of the central nervous system distinct from that of the rest of the body. Unfortunately, the blood-brain barrier begins to leak in later life, and the inappropriate passage of cells and molecules into the brain results in both chronic inflammation and more subtle processes of damage and disarray. The consensus is that this contributes to the development of neurodegenerative conditions and consequent dementia, though there is some debate over where exactly this fits in the hierarchy and causality of effects.
What causes the blood-brain barrier to break down? That is a question without a definitive answer, as for so many of the manifestations of aging. Researchers here provide evidence for rising levels of acid sphingomyelinase (ASM) to be important, demonstrating this in mice via artificially increased and decreased levels of ASM. We might then ask what causes increased ASM in old mice, but it usually takes years for researchers to follow the chain of cause and consequence to to the next point of interest, when working backwards from the end state in this manner.
Aging is related to progressive deterioration of central nervous system function and contributes to the pathogenesis of neurodegenerative disease. Previous studies have implicated alterations in the molecular mechanisms of aging with changes in the brain environment such as abnormal aggregation of proteins, neuronal loss, neuroinflammation, and cognitive deficits. The dysfunctions in aging could lead to neurodegenerative disease including mild cognitive impairment, cerebrovascular disease, Parkinson's disease, and Alzheimer's disease. In particular, disruption of the blood-brain barrier (BBB) is one of several major pathological features of these age-related neurodegenerative diseases. Moreover, many studies have demonstrated that BBB dysfunction may be a cause or consequence of neurodegeneration.
Acid sphingomyelinase (ASM), encoded by the Smpd1 gene, plays an important housekeeping role in sphingolipid metabolism and is known to regulate cell apoptosis, proliferation, and differentiation. Although ASM is expressed in virtually all cell types under normal conditions, ASM secreted from endothelial cells (ECs) is significantly associated with numerous diseases. ECs are the major cell type forming the BBB, along with pericytes and astrocytes, and the interaction between ECs and other neuronal cells is critical for the maintenance of neurological health in the brain. Previous studies have suggested that an increase in ASM activity may contribute to age-related brain damage. Nevertheless, the specific role of ASM in maintaining the integrity of the BBB and/or age-related neurodegeneration remains unclear.
In a recent study, we for the first time demonstrated that ASM derived from ECs plays a central role in aging-induced BBB disruption and neurodegeneration. Higher ASM activity was detected in plasma from older individuals (65-90 years) compared with plasma from their younger counterparts (24-45 years). We also confirmed similar results in plasma derived from old mice (20-months). The robust elevation in ASM levels in the brains of old mice was associated with microvessels, and ECs derived from microvessels were the main contributors for elevated ASM activity. These results indicated that ASM activity increased in aged plasma and brain ECs, and could affect brain dysfunction in the process of aging.
Old Smpd1 +/- mice, in which ASM is genetically inhibited, exhibited a significant reduction in ASM activity in the plasma and brain ECs. In addition, capillary density in the brains of older mice was decreased by EC death, while old Smpd1 +/- mice exhibited higher capillary density. BBB permeability was also increased in the brains of old mice. In contrast, a substantial decrease in permeability in old Smpd1 +/- mice was observed. Moreover, the leakiest vessels in the brain did not exhibit an apoptotic signal in both old mice and old Smpd1 +/- mice, indicating that the death of ECs caused by ASM was not the main cause of BBB disruption in aging.
In conclusion, our findings suggest a central role for ASM as a regulator of BBB integrity and neuronal function in aging, as well as highlight the potential of ASM as a drug target for anti-aging. To date, few inhibitors that can directly inhibit ASM have been found; nevertheless, highly potent and selective ASM inhibitors are anticipated to be developed in the future. Therefore, further studies investigating the development of functional ASM inhibitors may be highly valuable for understanding the anti-aging process and for the treatment of various age-related neurodegenerative diseases.