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.
Keywords:
ApoE4; Na+/H+ exchanger; amyloid beta; histone deacetylase; trichostatin A.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / genetics
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism*
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Animals
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Apolipoprotein E4 / genetics
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Apolipoprotein E4 / metabolism*
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Astrocytes / metabolism*
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Astrocytes / pathology
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Ataxia / drug therapy
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Ataxia / genetics
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Ataxia / metabolism
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Ataxia / pathology
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Endosomes / genetics
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Endosomes / metabolism*
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Endosomes / pathology
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Epigenesis, Genetic*
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Epilepsy / drug therapy
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Epilepsy / genetics
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Epilepsy / metabolism
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Epilepsy / pathology
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Genetic Diseases, X-Linked / drug therapy
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Genetic Diseases, X-Linked / genetics
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Genetic Diseases, X-Linked / metabolism
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Genetic Diseases, X-Linked / pathology
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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Humans
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Hydrogen-Ion Concentration
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Intellectual Disability / drug therapy
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Intellectual Disability / genetics
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Intellectual Disability / metabolism
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Intellectual Disability / pathology
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Low Density Lipoprotein Receptor-Related Protein-1
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Mice
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Mice, Knockout
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Microcephaly / drug therapy
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Microcephaly / genetics
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Microcephaly / metabolism
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Microcephaly / pathology
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Ocular Motility Disorders / drug therapy
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Ocular Motility Disorders / genetics
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Ocular Motility Disorders / metabolism
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Ocular Motility Disorders / pathology
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Receptors, LDL / genetics
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Receptors, LDL / metabolism
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Sodium-Hydrogen Exchangers / genetics
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Sodium-Hydrogen Exchangers / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Amyloid beta-Peptides
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Apolipoprotein E4
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Histone Deacetylase Inhibitors
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Low Density Lipoprotein Receptor-Related Protein-1
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Lrp1 protein, mouse
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NHE6 protein, mouse
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Receptors, LDL
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Sodium-Hydrogen Exchangers
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Tumor Suppressor Proteins
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Hdac5 protein, mouse
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Histone Deacetylases
Supplementary concepts
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Mental Retardation, X-Linked, Syndromic, Christianson Type