Dr. Jekyll and Mr. Hyde: ApoE explains opposing effects of neuronal LRP1
Michael R. Strickland, David M. Holtzman
Michael R. Strickland, David M. Holtzman
Published February 11, 2019
Citation Information: J Clin Invest. 2019;129(3):969-971. https://doi.org/10.1172/JCI127578.
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Commentary

Dr. Jekyll and Mr. Hyde: ApoE explains opposing effects of neuronal LRP1

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia, and its pathogenesis is initiated by the accumulation of amyloid-β (Aβ) into extracellular plaques. Apolipoprotein E4 (ApoE4) is the largest genetic risk factor for sporadic AD and contributes to AD pathogenesis by influencing clearance and seeding of the initial aggregation of Aβ. In this issue of the JCI, Tachibana et al. investigated the relationship between neuronal LRP1 expression and ApoE4-mediated seeding of Aβ and showed that knockout of neuronal LRP1 prevents the increase in Aβ pathology caused by ApoE4 expression. These findings give insight into potential therapeutic targets for the preclinical phase of AD and the pathogenesis of Aβ pathology.

Authors

Michael R. Strickland, David M. Holtzman

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Figure 1

ApoE4 seeding of Aβ.

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ApoE4 seeding of Aβ. (A) ApoE4 seeds Aβ aggregation in the presence of L...
(A) ApoE4 seeds Aβ aggregation in the presence of LRP1. (i) ApoE4 and Aβ compete for binding to HSPGs. (ii) LRP1 binds lipidated ApoE4, which is then endocytosed. (iii) Recycling endosomes are sites of Aβ production. ApoE4 may interact with Aβ to seed its aggregation. (iv) Aβ and lipidated ApoE4 are degraded in lysosomes. (v) Delipidated ApoE4 seeds the aggregation of Aβ. (vi) Aggregated ApoE4 and Aβ are released into the extracellular space. (B) Neuronal LRP1 knockout prevents ApoE4 seeding of Aβ. In the absence of LRP1 (i), ApoE4 associates with HSPGs and blocks binding of Aβ. (ii) Less ApoE4 is endocytosed (iii). ApoE4 contributes less to Aβ seeding, and more Aβ is degraded through the lysosomal pathway.