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Amyloid Clearance Defect in Apoe4 Astrocytes Is Reversed by Epigenetic Correction of Endosomal Ph

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Amyloid Clearance Defect in Apoe4 Astrocytes Is Reversed by Epigenetic Correction of Endosomal Ph Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH Hari Prasada and Rajini Raoa,1 aDepartment of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 Edited by Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany, and approved June 6, 2018 (received for review January 28, 2018) Endosomes have emerged as a central hub and pathogenic driver ability (7–9). Patients who have CS also show striking age- of Alzheimer’s disease (AD). The earliest brain cytopathology in dependent neurodegeneration, with prominent glial pathology neurodegeneration, occurring decades before amyloid plaques and phosphorylated tau deposits (7). Female carriers have and cognitive decline, is an expansion in the size and number of learning difficulties and behavioral issues, and some present with endosomal compartments. The strongest genetic risk factor for low Mini-Mental State Examination scores suggestive of early sporadic AD is the e4 allele of Apolipoprotein E (ApoE4). Previous cognitive decline (10). Interestingly, NHE6 was among the most studies have shown that ApoE4 potentiates presymptomatic endo- highly down-regulated genes (up to sixfold) in the elderly (70 y) somal dysfunction and defective endocytic clearance of amyloid brain, compared with the adult (40 y) brain (11). These obser- beta (Aβ), although how these two pathways are linked at a cel- vations led us to consider a broader role for NHE6 in neuro- lular and mechanistic level has been unclear. Here, we show that degenerative disorders, including Alzheimer’s disease (AD), a aberrant endosomal acidification in ApoE4 astrocytes traps the major cause of dementia in the elderly. Consistent with this hy- low-density lipoprotein receptor-related protein (LRP1) within in- pothesis, a coexpression analysis of quantitative trait loci in AD tracellular compartments, leading to loss of surface expression and brains revealed NHE6 as a top hub transcript, with 202 network Aβ clearance. Pathological endosome acidification is caused by + + connections and a plethora of potential downstream effects (12). A e4 risk allele-selective down-regulation of the Na /H exchanger knowledge-based approach for predicting gene–disease associa- isoform NHE6, which functions as a critical leak pathway for endo- tions also identified a link between NHE6 and early-stage AD (13). PHYSIOLOGY KO somal protons. In vivo, the NHE6 knockout (NHE6 ) mouse model Stronger evidence emerged from a recent analysis of the meta- showed elevated Aβ in the brain, consistent with a causal effect. stable aggregation-prone proteome in AD brains that identified Increased nuclear translocation of histone deacetylase 4 (HDAC4) NHE6 as a key component of the proteostasis machinery associ- in ApoE4 astrocytes, compared with the nonpathogenic ApoE3 ated with amyloid plaques and neurofibrillary tangles containing allele, suggested a mechanistic basis for transcriptional down- amyloid beta (Aβ) peptide and tau protein, respectively (14). regulation of NHE6. HDAC inhibitors that restored NHE6 expression Petsko and coworkers (15) recently proposed that endosomal normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking, “traffic jams” are the unifying mediators of downstream pathology and amyloid clearance. Thus, NHE6 is a downstream effector of in AD and interventions designed to “unjam” the endosome have ApoE4 and emerges as a promising therapeutic target in AD. These high therapeutic promise. Endosomal aberrations, evidenced by observations have prognostic implications for patients who have enlarged and more numerous endosomes, are the earliest de- Christianson syndrome with loss of function mutations in NHE6 tectable brain cytopathology, emerging several decades before and exhibit prominent glial pathology and progressive hallmarks cognitive dysfunction is apparent in a subset of neurodegenerative of neurodegeneration. disorders, including AD, Niemann–Pick type C, and Down syn- drome (16–19). Genes associated with endosomal trafficking have trichostatin A | amyloid beta | ApoE4 | Na+/H+ exchanger | histone deacetylase Significance he endosome is a central hub for incoming and outgoing traffic Alzheimer’s disease is the most common cause of dementia in and a key recycling/degradation sorting station. Transit through T the elderly. Most cases occur sporadically, with 40–65% of pa- the endolysosomal system is accompanied by an increasingly acidic tients carrying at least one copy of the E4 allele of Apolipopro- pH gradient that controls receptor–ligand uncoupling, vesicle tein E. Because no drug exists that can halt disease progress, budding, exosome formation, membrane turnover, enzyme activa- there is strong interest in understanding the presymptomatic tion, nutrient uptake, and cellular signaling (1). As a defining role of endosomes. We show that excessive endosomal acidifi- feature of compartmental identity and function, the pH of the cation in ApoE4 astrocytes is caused by downregulation of the endolysosomal lumen is precisely set by a balance between proton + + + + Na /H exchanger NHE6 and results in defective clearance of pump and leak pathways (2). The discovery of endosomal Na /H amyloid beta (Aβ) peptide by intracellular sequestration of the exchangers (eNHEs) first in yeast and soon after in plants and LRP1 receptor. Epigenetic modifiers restore NHE6 expression to metazoans, including mammals, established their evolutionarily alkalinize endosomal pH, increase surface expression of LRP1, conserved role as a leak pathway for protons in compartmental pH β + + and correct A clearance in astrocytes. Thus, endosomal pH homeostasis (2–4). Na /H exchangers are estimated to have ex- emerges as a target for the correction of amyloid disorders. ceptionally high transport rates of ∼1,500 ions per second (5), so that even small perturbations in expression or activity result in Author contributions: H.P. and R.R. designed research; H.P. performed research; H.P. and dramatic changes in the ionic milieu within the limited confines of R.R. analyzed data; and H.P. and R.R. wrote the paper. the endosomal lumen. The authors declare no conflict of interest. As a testament to the central role of the endosome at the This article is a PNAS Direct Submission. crossroads of cellular traffic, mutations in eNHEs have been Published under the PNAS license. linked to a host of neurodevelopmental and neurodegenerative 1To whom correspondence should be addressed. Email: [email protected]. + + disorders (2, 6). Loss-of-function mutations in the Na /H ex- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. changer NHE6 (SLC9A6) cause Christianson syndrome (CS), an 1073/pnas.1801612115/-/DCSupplemental. X-linked disorder characterized by autism and intellectual dis- www.pnas.org/cgi/doi/10.1073/pnas.1801612115 PNAS Latest Articles | 1of10 Downloaded by guest on October 1, 2021 also been implicated as major risk factors in AD (20). Indeed, the Appendix, Fig. S3 A and B). Meta-analysis of nine independent strongest genetic risk factor in sporadic AD is the e4 allele of gene expression studies from anatomically and functionally dis- Apolipoprotein E (ApoE4), which potentiates both presymptom- tinct brain regions, comprising a total of 103 AD and 87 control atic endosomopathy and defective clearance of Aβ (21–25), al- postmortem brains, also showed no significant changes in LRP1 though how these two pathways are linked at a cellular level has gene expression in AD (SI Appendix, Fig. S3 C and D). Consis- been unclear. tent with these findings, we observed no differences in LRP1 Here, we show that a pathological acidification of endosomal pH transcript (SI Appendix, Fig. S3E) and total LRP1 protein ex- in humanized mouse ApoE4 astrocytes is caused by the selective pression between ApoE3 and ApoE4 astrocytes (SI Appendix, down-regulation of NHE6. This leads to endosomal sequestration Fig. S3 F and G). and cell surface loss of the Aβ receptor, low-density lipoprotein LRP1 undergoes constitutive endocytosis from the membrane receptor-related protein (LRP1). Increased nuclear translocation and recycling back to the cell surface (37). Therefore, we con- of the histone deacetylase 4 (HDAC4) in ApoE4 astrocytes can be sidered the possibility that alterations in LRP1 receptor recycling abrogated by HDAC inhibitors that restore NHE6 expression, could result in differences in plasma membrane expression. ApoE reroute LRP1 to the cell surface, and effectively restore defective isotype-specific surface expression of LRP1 was evaluated using amyloid clearance to nonpathological ApoE3 levels. Consistent four independent approaches (Fig. 2A). First, surface biotinylation with a proposed role in amyloid pathology, we found that in vivo revealed that plasma membrane expression of LRP1 receptor in Aβ levels were significantly higher in the brains of NHE6 knockout ApoE4 astrocytes was lower by ∼50% (Fig. 2B). Second, an an- (NHE6KO) mice. Our findings could have prognostic implications tibody directed against an external epitope of LRP1 to quantify for patients with CS and suggest therapeutic strategies for the surface expression in live cells by flow cytometry analysis showed a treatmentofamyloiddisorders(7,26). reduction of LRP1-positive cells by ∼55% in ApoE4 astrocytes (Fig. 2C)andby∼51% in patient-derived ApoE4/4 fibroblasts (SI Results Appendix,Fig.S2D). Third, this was confirmed by confocal mi- ApoE4 Astrocytes Have Cargo-Specific Defects
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