Editors' ChoiceAlzheimer’s Disease

Protein Clearance Ain’t What It Used to Be

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Science Translational Medicine  24 Dec 2014:
Vol. 6, Issue 268, pp. 268ec220
DOI: 10.1126/scitranslmed.aaa3467

Several age-related neurodegenerative diseases are characterized by the accumulation and aggregation of misfolded proteins. In Alzheimer's disease (AD), amyloid-β peptide (Aβ) is secreted from cells and forms extracellular aggregates and eventually plaques—a pathological hallmark of the disease. In typical sporadic AD, it remains unclear whether Aβ accumulation results from overproduction or impaired clearance from the brain. Furthermore, it is not understood how aging—the primary risk factor for AD—influences Aβ clearance.

Recently, researchers led by Nedergaard have developed an new system that allows them to measure the flow of extracellular fluid out of the brain, a process they term “glymphatic flow,” as it appears to be a brain-specific version of lymphatic drainage and requires the function of aquaporin-4 water channels expressed on glial cells that surround blood vessels. By injecting fluorescent tracers into the cerebrospinal fluid, one can measure how quickly these molecules are cleared from the brain by the glymphatic system.

Previously, this group demonstrated that glymphatic flow is important for ridding the brain of waste products, including damaged proteins, and that it was strongly regulated by the sleep-wake cycle. In the new work, the authors have shown that glymphatic flow in mice declines markedly with age. This decline was associated with an age-related change in the expression of glial aquaporin-4 channels, which became less associated with blood vessels. The investigators further demonstrated that the clearance of Aβ, which was injected into the brain, was significantly impaired in old mice, suggesting that age-related disruption of glymphatic flow might facilitate Aβ accumulation in the brain by limiting clearance.

Although this study provides new insights into a possible mechanism of AD pathogenesis, several issues remain. First, the clearance of exogenous Aβ that has been injected into the brain parenchyma as a bolus may not reflect the dynamics of clearance of endogenously derived Aβ, which is secreted from synapses. It also is unclear if all proteins and other solutes are cleared equivalently by glymphatic flow or if selectivity occurs. Last, glymphatic flow is not well understood in humans. However, these findings have potential diagnostic and therapeutic implications. Diagnostically, methods to quantify glymphatic clearance in humans could potentially be used as biomarkers of AD risk. Therapies that target glial function or other mechanisms to augment glymphatic flow might mitigate Aβ accumulation. More translational studies are needed to fully realize the potential of this new mechanism of protein clearance.

B. T. Kress et al., Impairment of paravascular clearance pathways in the aging brain. Ann. Neurol. 76, 845–861 (2014). [Abstract]

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