Editors' ChoiceAlzheimer’s Disease

β-amyloid can’t go with the flow

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Science Translational Medicine  07 Dec 2016:
Vol. 8, Issue 368, pp. 368ec195
DOI: 10.1126/scitranslmed.aal2804

Recent studies in rodents identified a brain-wide network of perivascular pathways called the glymphatic system that recirculates cerebrospinal fluid (CSF) through the brain parenchyma and clears interstitial solutes, such as β-amyloid (Aβ). Flow decreases through these perivascular pathways with advancing age. CSF and interstitial fluid are exchanged through the astroglial water channel aquaporin-4, and the expression of this channel is disrupted in the cerebrovasculature of human brains with Alzheimer’s disease. Since age is the greatest risk factor for Alzheimer’s disease, this suggests that decreasing Aβ clearance due to reduced CSF flow with age may increase Aβ concentration in the brain and therefore increase amyloid deposition.

To look for evidence of changes in aquaporin-4 expression and perivascular localization with aging and Alzheimer’s disease pathogenesis in humans, Zeppenfeld et al. examined postmortem frontal cortex tissue samples. 58 cognitively normal controls were either young (33 to 57 years old) or aged (61 to 96 years old), and 21 individuals had histopathologically confirmed Alzheimer’s disease (61 to 105 years old). Expression of aquaporin-4 was evaluated by western blot and localization by immunofluorescence in frozen and fixed frontal cortical tissue. The investigators found that increased aquaporin-4 expression was associated with advancing age. Reduced perivascular localization of aquaporin-4 was associated with Alzheimer’s disease pathology, specifically increased Aβ deposition, even after controlling for age.

Zeppenfeld et al. concluded that loss of perivascular aquaporin-4 localization renders the aging brain vulnerable to Aβ deposition because fluid flow through the glymphatic system is impeded. This finding suggests how changes in the glymphatic system may, in part, explain observed decreases in Aβ clearance and increases in Aβ deposition with age. There are several limitations in this study. First, the observed differences in aquaporin-4 expression and localization may be driven by Alzheimer’s disease pathology rather than a cause of the pathology. Second, the study examined only the frontal cortex and does not offer evidence to explain Alzheimer’s pathology in other brain regions, such as the hippocampus. Third, the glymphatic system has been demonstrated in rodents but awaits confirmation in humans. Despite these limitations, the current study provides compelling evidence for continued translational research in this exciting field.

D. M. Zeppenfeld et al., Association of perivascular localization of aquaporin-4 with cognition and Alzheimer Disease in aging brains. JAMA Neurol. 10.1001/jamaneurol.2016.4370 (2016). [Full Text]

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