Alzheimer’s disease is a degenerative condition that destroys connections between brain cells leading to memory loss, confusion and difficulties in thinking. Apolipoprotein E is a protein that carries fatty substances called lipids and cholesterol around the brain, and plays an important role in repair mechanisms. There are three major forms of Apolipoprotein E, and individuals who carry a version known as ApoE4 are up to 10 times more likely to develop Alzheimer’s disease than those who carry other variations.

In nerve cells, or neurons, Apolipoprotein E binds to a specific family of receptors. One of these receptors, called Apoer2, is found in the synaptic gap between neurons, where it regulates their activities. Both Apolipoprotein E and Apoer2 are taken into the cell within compartments known as endosomal vesicles. Usually, the Apoer2 receptor is quickly recycled back to the surface of the cell, but this recycling process is delayed in individuals with the ApoE4 version of Apolipoprotein E.

Apoer2 is just one of many different receptors on the surface of neurons that are taken into vesicles before being recycled back to the cell surface. The fluid inside these vesicles becomes progressively more acidic as they move through the cell. This process helps to control the interaction of these receptors with their binding partners and to regulate their movement and recycling. Here, Xian, Pohlkamp et al. investigated whether changing the acidity of vesicles in rat neurons could overcome the block in recycling Apoer2 – and other receptors that travel with Apoer2 in the same compartments – in the presence of ApoE4.

A protein called NHE6 is embedded in the membrane of vesicles called early endosomes and acts to make the vesicles less acidic. Xian, Pohlkamp et al. used drugs to block the activity of NHE6, which led to the vesicles becoming more acidic and allowed Apoer2 to be recycled faster. Using a genetic approach known as siRNA knockdown to decrease the amount of NHE6 produced in neurons also had a similar effect on Apoer2 recycling.

Together these findings suggest that drugs that make vesicles in neurons more acidic may have the potential to help prevent individuals that carry the ApoE4 protein from developing Alzheimer’s disease. Current drugs that target NHE6 also affect other molecules, which can often lead to side effects. A next step will be to develop tailor-made, small molecule drugs that can enter the brain efficiently and selectively block NHE6.

Over the course of the last 30 years, we have learned much about the genetics of Alzheimer’s disease (AD), yet the pathological mechanisms that cause the onset of the disease and that define its progression culminating in massive neurodegeneration and debilitating dementia remain poorly understood. We know that amyloid-β (Aβ), an aggregation-prone proteolytic processing product that consists of juxtamembrane sequences and approximately 2/3 of the transmembrane segment of the larger amyloid precursor protein (APP), plays a central role early on, while during later stages of the disease – through mechanisms that are completely obscure – the microtubule-associated protein τ begins to form intraneuronal aggregates, that is the neurofibrillary tangles, that can spread transsynaptically (Selkoe and Hardy, 2016). It is this τ-aggregation, not the amyloid plaques, which occur early in the disease process, that is thought to be primarily responsible for the neuronal cell death and brain mass loss and that most closely tracks with dementia progression. Before they become visible as the telltale plaques and tangles that cement the AD diagnosis for the pathologist, Aβ and τ are present as smaller oligomeric aggregates that can directly and profoundly impair neuronal functions, by disrupting synaptic Ca²⁺ homeostasis (Kuchibhotla et al., 2008). The resulting synaptic dysfunction is widely thought to represent the earliest stage of the AD pathogenic process and to be a major cause of its clinical manifestation as mild cognitive impairment (MCI) (Palop and Mucke, 2010; Shankar and Walsh, 2009).

Although AD almost certainly involves early Aβ accumulation, only a vanishingly small number of individuals suffering from the vicious and dominant early-onset form of AD carry mutations in APP (Campion et al., 1999). These missense mutations invariably increase Aβ production and lead to early plaque deposition, while a similarly small number of people have a genetic variation in APP that lowers Aβ production and hence protects from the much more frequent late-onset form of AD (LOAD) (Jonsson et al., 2012). Numerous other genetic determinants contribute to the bulk of LOAD, which typically develops after the 6th decade. The most important of these is Apolipoprotein E ε4 (ApoE4) genotype (Corder et al., 1993; Strittmatter et al., 1993).

ApoE is a lipid and cholesterol carrying protein that is primarily produced by the liver and is responsible for plasma lipid homeostasis (Mahley, 1988). It occurs in three major isoforms in humans known as ApoE2, ApoE3 and ApoE4, with ApoE3 being the most frequent allele (~77% homozygosity) followed by ApoE4 (~15 – 20% allele frequency) which is present in >50% of LOAD (Liu et al., 2013). The effect of ApoE4 on Aβ accumulation through impaired Aβ turnover, increased aggregation and thus plaque formation is allele dosage-dependent and this can partly explain its effect on the earlier age of disease onset (Corder et al., 1993). However, ApoE4 can independently impair synapse function and Ca²⁺ homeostasis by disrupting the endocytic transport and recycling of synaptic ApoE receptors and the excitatory AMPA and NMDA type glutamate receptors that are regulated by those ApoE receptors and that are consequently trapped with them in the same vesicles (Chen et al., 2010).

Most ApoE receptors, which are all members of the low-density lipoprotein (LDL) receptor gene family, are expressed in the brain and several are intrinsic components of excitatory synapses where they are present in the presynaptic and postsynaptic compartments (reviewed in Lane-Donovan et al., 2014; Pohlkamp et al., 2017). Of these, ApoE receptor-2 (Apoer2, a.k.a. LRP8) is the best characterized. It is present both pre- as well as postsynaptically where it primarily functions as a receptor for Reelin (Bal et al., 2013; Beffert et al., 2005; Lane-Donovan and Herz, 2017). Reelin is a large secreted protein that is essential for the formation of cortical layers during embryonic brain development where it serves as a guidance molecule in the regulation of neuronal migration (D'Arcangelo et al., 1995; Del Río et al., 1997). As the brain continues to develop and mature postnatally, its expression pattern changes and Reelin is now produced by a subset of GABAergic interneurons that are interspersed throughout the neocortex and the hippocampus (Alcántara et al., 1998; Pesold et al., 1998; Pohlkamp et al., 2014). In the adult brain, this secreted Reelin now functions as a neuromodulator by signaling through Apoer2 and its closely related family member Vldlr to activate Src-family tyrosine kinases directly in the synapse, which results in increased Ca²⁺ influx through NMDA receptors and thus the robust elevation and maintenance of synaptic potentiation (Chen et al., 2005; Hiesberger et al., 1999; Wasser and Herz, 2017). This is the key event in the maintenance of synaptic homeostasis that is impaired by ApoE4 and which occurs independent of Aβ accumulation (Chen et al., 2005). Indeed, ApoE4-specific alterations in brain structure have been found in <2 year old children (Dean et al., 2014; Shaw et al., 2007).

The molecular basis by which ApoE4 causes the disruption of normal endosomal vesicle transport and recycling is most likely the result of its propensity to unfold and assume a ‘molten-globule’ conformation upon entering an acidic environment (Morrow et al., 2002). ApoE4 differs from ApoE3 by a single amino acid, which alters its isoelectric point to coincide with the pH of ~6.5 that is present in the early endosome (Casey et al., 2010; Ordovas et al., 1987). We hypothesized that this isoelectric charge neutralization would make ApoE4 prone to aggregation, which could be the molecular basis for the ApoE4-induced and gene dosage-dependent recycling defect.

pH in the early endosome is maintained by the opposing functions of the proton pump, which decreases vesicular pH, and the Na⁺/H⁺ exchanger NHE6, which increases it (Fuster and Alexander, 2014). Here, we have investigated the role of NHE6 inhibition as a means of lowering endosomal pH, away from the isoelectric point of ApoE4. We found that this simple pharmacological intervention releases the endosomal ApoE4 block, restores the normal trafficking of ApoE receptors and glutamate receptors in neurons and corrects the functional defects in vitro and in vivo. These findings suggest NHE6 inhibition as a novel rational therapeutic approach for reversing the AD risk imposed by ApoE4.

We have used insights into the molecular structure and biophysical properties of ApoE isoforms to develop a novel rational drug identification approach to reverse the increased AD risk inherent to the ApoE4 allele. In earlier studies, we found that ApoE4 impairs endosomal vesicle recycling (Chen et al., 2010). While investigating the molecular basis for this trafficking delay, we recognized that the predicted isoelectric point of ApoE4 closely matches the prevailing pH in the early endosome. We hypothesized that ApoE4, which is known to assume a molten-globule state under low pH conditions, might lose solubility as it enters the lower pH environment of the early endosome. This in turn could impair vesicle propagation through the endosomal recycling pathway and result in the observed sequestration of ApoE receptors and associated excitatory neurotransmitter receptors in cortical neurons (Chen et al., 2010). We predicted that changing endosomal pH away from the isoelectric point of ApoE4 should prevent this isoelectric precipitation and resolve the recycling block. Since raising endosomal pH using alkalinizing agents, such as ammonium chloride or chloroquine, is known to arrest endosomal trafficking by preventing lipoprotein release from lipoprotein receptors (Goldstein et al., 1985), we investigated approaches to lower endosomal pH instead. Two possible mechanisms for this are i) activation of the proton pump, or ii) preventing proton efflux from the endosome by inhibiting the endosomal sodium/potassium hydrogen exchanger NHE6. Our results now show that pharmacological as well as genetic inhibition of NHE activity in the early endosome is sufficient to completely resolve the ApoE4 induced endosomal recycling block and restore the normal cell surface recycling rate of the synaptic ApoE receptor Apoer2 and the excitatory AMPA- and NMDA-type glutamate receptors that are regulated by Apoer2 and that traffic together with Apoer2 through the endosomal recycling compartments (illustrated by the model shown in Figure 9).

Previously, we and others have shown that ApoE4-KI mice exhibit enhanced LTP while the neuromodulator Reelin has no potentiating effect on LTP expression in this genotype (Durakoglugil et al., 2009), suggesting that ApoE4 impairs the physiological response to Reelin. Here, we show that NHE inhibition with EMD87580 in ApoE4-KI mice reverses the ApoE4 induced Reelin resistance (Figure 7) and restores the ability of Reelin to protect against Aβ toxicity (Figure 8). ApoE3-KI slices treated with EMD87580 exhibit increased LTP consistent with previous findings that have shown that the NHE inhibitor ethyl-isopropyl amiloride (EIPA) can enhance theta-burst-induced LTP (Rönicke et al., 2009). NHE activity was proposed to be a negative feedback mechanism that can regulate neuronal excitability as well as plasticity. In ApoE4-KI mice, EMD87580 decreased LTP to baseline levels of control ApoE3-KI mice and importantly LTP became now responsive to Reelin-facilitation. This observation suggests that it is the restoration of normal release of ApoE4 from Apoer2 in acidified endosomal compartments and the subsequent normalization of endosomal trafficking that reestablishes optimal synaptic homeostasis in the presence of ApoE4.

Although more than 20 genetic loci that modify the risk for late-onset AD have been discovered to date (Karch et al., 2014), ApoE4 genotype is by far the major genetic risk factor for late-onset AD besides aging, affecting almost 1/5^th of the human population, and hence it is clinically the most important one. The molecular mechanisms by which ApoE4 imposes this risk remain under debate. Early work following the seminal discovery of this striking genetic association by the Roses group (Corder et al., 1993) focused on the differential ability of ApoE isoforms to interact with Aβ and affect fibril formation. Efforts in our own laboratory were based on the rationale that ApoE receptors, that is the LDL receptor gene family, are highly likely to be involved in the disease process. This hypothesis was the initial driver that defined a plethora of surprising functions of LDL receptor-related proteins (LRPs) in the central and peripheral nervous system (Bal et al., 2013; Beffert et al., 2005; Bell et al., 2012; Choi et al., 2013; Kim et al., 2008; Lane-Donovan and Herz, 2017; Liu et al., 2013; Liu et al., 2007; Liu et al., 2011; May et al., 2004; Nakajima et al., 2013; Pohlkamp et al., 2015; Pohlkamp et al., 2017; Trommsdorff et al., 1999; Wasser and Herz, 2017; Wasser et al., 2014; Weeber et al., 2002; Zhang et al., 2008; Zhao et al., 2017). They included unprecedented roles as direct signal-transducing receptors (Hiesberger et al., 1999; Trommsdorff et al., 1999) and regulators of central and peripheral synaptic transmission (Beffert et al., 2005; Choi et al., 2013; Weeber et al., 2002) and have established a strong rationale and mechanistic basis by which ApoE isoforms and ApoE receptors can directly affect synaptic homeostasis, neuronal survival and thus the cognitive impairment and progressive neurodegeneration that underlie LOAD.

Presynaptic and postsynaptic vesicle recycling is a central element of synaptic transmission (Harris et al., 2012; Kawasaki et al., 2000; Robinson et al., 1993; Sontag et al., 1994; Sudhof, 2004). Intriguingly, enlarged endosomal compartments and impaired endolysosomal functions are also a prominent feature of APP expression, processing and early AD (Cataldo et al., 2000; Decourt et al., 2013; Ishigaki et al., 2000; Nixon et al., 2001; Salehi et al., 2006). Our original finding that ApoE isoforms can differentially impair synapse functions by trapping postsynaptic (and possibly also presynaptic) recycling vesicles that contain ApoE receptors was inspired by the original observations of Heeren, Beisiegel and colleagues who first described a prolonged intracellular retention of ApoE4 in a hepatoma cell line (Heeren et al., 2004). In a series of experiments, we showed that ApoE4 impairs NMDA receptor activation and neuronal Ca²⁺ conductance by the neuromodulator and ApoE receptor ligand Reelin. This was caused by the dramatically delayed recycling of the Reelin receptor and regulator of glutamate receptor trafficking Apoer2 in the presence of ApoE4 and, notably, also to a smaller extent by ApoE3 and less by ApoE2 (Chen et al., 2010). The dramatically altered recycling kinetics in the presence of ApoE4 lead to an altered state of synaptic homeostasis, which we have termed ‘Reelin resistance’ (Lane-Donovan et al., 2014) and which prevents the synapse from adequately adapting to the rising levels of synapse-suppressing Aβ oligomers as they accumulate in the aging brain. The compensatory increase in synaptic and network activity (Palop and Mucke, 2010) would further drive Aβ production (Cirrito et al., 2008), thereby accelerating a self-reinforcing cycle that would be predicted to contribute to the earlier amyloid accumulation in ApoE4 carriers. Moreover, a second mechanism by which impaired ApoE4-containing vesicle recycling would be predicted to contribute to accelerated amyloid accumulation and plaque deposition (Fagan et al., 2002) involves the reduced turnover rate of Aβ in the brains of ApoE4 targeted replacement mice (Castellano et al., 2011) and humans (Wildsmith et al., 2012).

Recently, the Bu laboratory reported a direct interaction of ApoE with insulin receptors in the brain, which also resulted in their intracellular retention and impaired insulin signaling (Zhao et al., 2017). Although in our experiments we did not detect impaired insulin receptor trafficking (Figure 2B and C), and there is also no evidence that ApoE4 carriers are predisposed to the predicted insulin resistance that would be expected to result from intracellular insulin receptor trapping, these data add nevertheless further support to our model which postulates impaired neuronal endosomal vesicle trafficking as the root cause for the increased AD risk imposed by ApoE4 (Chen et al., 2005; Chen et al., 2010; Lane-Donovan and Herz, 2017; Lane-Donovan et al., 2014).

Our data indicate that ApoE4 induces endosomal trafficking deficits. Consistently, alkalinizing drugs, such as ammonium chloride or chloroquine, which increase vesicular pH in the cell, lead to an arrest of endosomal trafficking by preventing lipoprotein release from their receptors (Goldstein et al., 1985). We therefore chose to explore the effect of acidification of endosomes as a means to overcome the trafficking impairments caused by ApoE4. By contrast, a recent study in astrocytes has proposed that the presence of ApoE4 results in endosomal acidification caused by NHE6 reduction, leading to impaired Aβ-clearance (Prasad and Rao, 2018). These authors further reported that increased NHE6 expression, which would elevate endosomal pH, induced by HDAC-inhibition alleviated the impaired of Aβ-clearance.

We show here that Aβ-induced synaptic impairment could be abolished by the NHE inhibitor EMD87580 (Figure 8). Both studies show that manipulation of endosomal pH can affect the endosomal trafficking of ApoE. We show that in neurons this alters cell surface Apoer2 expression levels and thus synaptic plasticity. Prasad and Rao (2018) showed that in astrocytes a similar mechanism may mediate Aβ clearance involving the ApoE receptor Lrp1. The isoelectric point of ApoE4, but not ApoE2 and ApoE3, matches the physiological pH present in early endosomes and reduced solubility at or near their isoelectric point is a general property of many proteins including insulin (Wintersteiner and Abramson, 1933). In contrast to ApoE2 and ApoE3, the conformation of ApoE4 in the early endosome might be particularly vulnerable, because it alone has been shown to be prone to unfolding under low pH conditions resulting in a molten-globule state (Morrow et al., 2002).

Along the same lines, ApoE4 increased the number and size of early endosomes in AD patients (Cataldo et al., 2000) and in neurons derived from induced pluripotent stem cells (Lin et al., 2018). These data suggest that manipulating endosomal pH represents a promising therapeutic target to improve endosomal trafficking deficits induced by ApoE4.

In order to fully address the physiological functions of NHE6 and understand its role in ApoE4 induced neurodegenerative processes, it will be necessary to develop NHE6 specific inhibitors that can pharmacologically modulate NHE6 - as opposed to switching it on or off in a binary fashion - to achieve the optimal pH for ApoE4 trafficking without undue interference with essential cellular transport processes or the function of other NHEs. Such inhibitors must also be capable of crossing the blood brain barrier, something the presently available non-specific inhibitor classes are incapable of doing.

In summary, we have shown that the conformational change of ApoE4 to a molten-globule state (Morrow et al., 2002) in a low pH environment, which correlates with the impaired endosomal vesicle recycling in the presence of ApoE4 (Chen et al., 2010; Heeren et al., 2004; Lane-Donovan and Herz, 2017; Lane-Donovan et al., 2014; Rellin et al., 2008), can be reversed by changing endosomal pH (Herz et al., 2010). As a mechanistic basis we propose the propensity of many proteins to lose hydrophilicity at or near their isoelectric point, which makes them prone to aggregation and precipitation, a seminal discovery that made the purification of insulin on an industrial scale possible (Wintersteiner and Abramson, 1933). By altering endosomal pH, ApoE4 maintains its solubility and the recycling block is avoided. This simple biophysical property can explain in a straightforward manner many observations by which ApoE isoforms differentially affect neuronal functions and AD-relevant mechanisms. Our findings also point toward NHE6-specific inhibitors as a rational basis for a novel approach to erase the AD risk imposed by ApoE4.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Xunde Xian

   1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
   2. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Contributed equally with

   Theresa Pohlkamp

   For correspondence

   Xunde.xian@utsouthwestern.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3059-1254

2. Theresa Pohlkamp

   1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
   2. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing—review and editing

   Contributed equally with

   Xunde Xian

   Competing interests

   No competing interests declared

3. Murat S Durakoglugil

   1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
   2. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4483-8166

4. Connie H Wong

   1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
   2. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6452-7966

5. Jürgen K Beck

   Jkb Consult Inc SPRL, Brussels, Belgium

   Contribution

   Conceptualization, Funding acquisition

   Competing interests

   No competing interests declared

6. Courtney Lane-Donovan

   1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
   2. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States

   Contribution

   Resources, Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9504-8346

7. Florian Plattner

   1. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States
   2. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, United States

   Contribution

   Formal analysis, Supervision, Validation, Project administration, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3150-1866

8. Joachim Herz

   1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
   2. Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, United States
   3. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
   4. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, United States

   Contribution

   Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   joachim.herz@utsouthwestern.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8506-3400

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