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Research Article

Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH

Hari Prasad and View ORCID ProfileRajini Rao
  1. aDepartment of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205

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PNAS July 10, 2018 115 (28) E6640-E6649; first published June 26, 2018; https://doi.org/10.1073/pnas.1801612115
Hari Prasad
aDepartment of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
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Rajini Rao
aDepartment of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
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  • ORCID record for Rajini Rao
  • For correspondence: rrao@jhmi.edu
  1. Edited by Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany, and approved June 6, 2018 (received for review January 28, 2018)

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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.

  • trichostatin A
  • amyloid beta
  • ApoE4
  • Na+/H+ exchanger
  • histone deacetylase

Footnotes

  • ↵1To whom correspondence should be addressed. Email: rrao{at}jhmi.edu.
  • Author contributions: H.P. and R.R. designed research; H.P. performed research; H.P. and R.R. analyzed data; and H.P. and R.R. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1801612115/-/DCSupplemental.

Published under the PNAS license.

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Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH
Hari Prasad, Rajini Rao
Proceedings of the National Academy of Sciences Jul 2018, 115 (28) E6640-E6649; DOI: 10.1073/pnas.1801612115

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Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH
Hari Prasad, Rajini Rao
Proceedings of the National Academy of Sciences Jul 2018, 115 (28) E6640-E6649; DOI: 10.1073/pnas.1801612115
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Proceedings of the National Academy of Sciences: 115 (28)
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