Editors' ChoiceAlzheimer’s Disease

Clearing the way to a healthy brain

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Science Translational Medicine  22 Mar 2017:
Vol. 9, Issue 382, eaan0767
DOI: 10.1126/scitranslmed.aan0767

Abstract

Astrocytic low-density lipoprotein receptor–related protein 1 is a key player in β-amyloid clearance.

β-amyloid (Aβ) is a neuropathological hallmark of both familial and late-onset Alzheimer’s disease (AD). The primary mechanisms of Aβ accumulation may differ between the two forms, with increased Aβ production a signature of familial AD and decreased Aβ clearance more predominant in the more common late-onset AD. Clinically available neuroimaging techniques now allow for detection of cerebral Aβ years before cognitive decline, and a better understanding of mechanisms involved in Aβ clearance may be critical for modifying disease risk in individuals deemed to have increased cerebral amyloid.

A recent study by Liu et al. reveals an important mechanism for amyloid clearance that involves low-density lipoprotein receptor–related protein 1 (LRP1). LRP1 is aberrantly expressed in AD brain and plays critical roles in endocytosis and signal transduction pathways. These functions likely underlie the relationship between LRP1 and diverse cellular processes that are altered in AD, such as insulin signaling, lipid homeostasis, and Aβ metabolism. In this study, knockdown of LRP1 in primary astrocytes decreased both Aβ degradation and the proteases that are critical to this degradation, including insulin degrading enzyme and metalloproteases 2 and 9. Subsequent in vivo experiments in amyloid mouse models showed that an astrocyte-specific LRP1 knockout increased amyloid plaque load and increased inflammatory markers in both cortex and hippocampus. This differed from the investigators’ earlier work, where neuron-specific LRP1 depletion did not affect proteases and did not increase Aβ in the hippocampus, only the cortex. Hippocampal atrophy is a key feature of AD, and LRP1 modulation of proteolytic enzymes in astrocytes may be key in preventing Aβ deposition in this region. No effect on amyloid production was observed in the current study, further indicating that LRP1’s effects on Aβ plaque load are due to clearance.

Although it remains to be seen whether these findings will translate from the amyloid mouse model, this study shows that astrocytic LRP1 plays a key role in cellular uptake and degradation of Aβ. It further indicates that LRP1 and related processes could be targets for therapies aimed at clearing brain amyloid.

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