Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH
Edited by Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany, and approved June 6, 2018 (received for review January 28, 2018)
Significance
Alzheimer’s disease is the most common cause of dementia in the elderly. Most cases occur sporadically, with 40–65% of patients carrying at least one copy of the E4 allele of Apolipoprotein E. Because no drug exists that can halt disease progress, there is strong interest in understanding the presymptomatic role of endosomes. We show that excessive endosomal acidification in ApoE4 astrocytes is caused by downregulation of the Na+/H+ exchanger NHE6 and results in defective clearance of amyloid beta (Aβ) peptide by intracellular sequestration of the LRP1 receptor. Epigenetic modifiers restore NHE6 expression to alkalinize endosomal pH, increase surface expression of LRP1, and correct Aβ clearance in astrocytes. Thus, endosomal pH emerges as a target for the correction of amyloid disorders.
Abstract
Endosomes have emerged as a central hub and pathogenic driver of Alzheimer’s disease (AD). The earliest brain cytopathology in neurodegeneration, occurring decades before amyloid plaques and cognitive decline, is an expansion in the size and number of endosomal compartments. The strongest genetic risk factor for sporadic AD is the ε4 allele of Apolipoprotein E (ApoE4). Previous studies have shown that ApoE4 potentiates presymptomatic endosomal dysfunction and defective endocytic clearance of amyloid beta (Aβ), although how these two pathways are linked at a cellular and mechanistic level has been unclear. Here, we show that aberrant endosomal acidification in ApoE4 astrocytes traps the low-density lipoprotein receptor-related protein (LRP1) within intracellular compartments, leading to loss of surface expression and Aβ clearance. Pathological endosome acidification is caused by ε4 risk allele-selective down-regulation of the Na+/H+ exchanger isoform NHE6, which functions as a critical leak pathway for endosomal protons. In vivo, the NHE6 knockout (NHE6KO) mouse model showed elevated Aβ in the brain, consistent with a causal effect. Increased nuclear translocation of histone deacetylase 4 (HDAC4) in ApoE4 astrocytes, compared with the nonpathogenic ApoE3 allele, suggested a mechanistic basis for transcriptional down-regulation of NHE6. HDAC inhibitors that restored NHE6 expression normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking, and amyloid clearance. Thus, NHE6 is a downstream effector of ApoE4 and emerges as a promising therapeutic target in AD. These observations have prognostic implications for patients who have Christianson syndrome with loss of function mutations in NHE6 and exhibit prominent glial pathology and progressive hallmarks of neurodegeneration.
Acknowledgments
We thank Drs. Robert Edwards and Julie Ullman (University of California, San Francisco) for providing mouse brains and Dr. David M. Holtzman (Washington University in St. Louis) for the gift of ApoE astrocytes. We thank Dr. Seth S. Margolis for helpful discussions and Richard L. Blosser for assistance with the flow cytometry analysis. This work was made possible by support from the Johns Hopkins Medicine Discovery Fund (R.R.). Additional support came from NIH grant DK054214 (to R.R.). H.P. is a Fulbright Fellow supported by the International Fulbright Science and Technology Award.
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© 2018. Published under the PNAS license.
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Published online: June 26, 2018
Published in issue: July 10, 2018
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Acknowledgments
We thank Drs. Robert Edwards and Julie Ullman (University of California, San Francisco) for providing mouse brains and Dr. David M. Holtzman (Washington University in St. Louis) for the gift of ApoE astrocytes. We thank Dr. Seth S. Margolis for helpful discussions and Richard L. Blosser for assistance with the flow cytometry analysis. This work was made possible by support from the Johns Hopkins Medicine Discovery Fund (R.R.). Additional support came from NIH grant DK054214 (to R.R.). H.P. is a Fulbright Fellow supported by the International Fulbright Science and Technology Award.
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This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH, Proc. Natl. Acad. Sci. U.S.A.
115 (28) E6640-E6649,
https://doi.org/10.1073/pnas.1801612115
(2018).
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