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.

1. 1. Alcántara S
   2. Ruiz M
   3. D'Arcangelo G
   4. Ezan F
   5. de Lecea L
   6. Curran T
   7. Sotelo C
   8. Soriano E

   (1998) Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse

   The Journal of Neuroscience 18:7779–7799.

   https://doi.org/10.1523/JNEUROSCI.18-19-07779.1998

   • PubMed
   • Google Scholar
2. 1. Bal M
   2. Leitz J
   3. Reese AL
   4. Ramirez DM
   5. Durakoglugil M
   6. Herz J
   7. Monteggia LM
   8. Kavalali ET

   (2013) Reelin mobilizes a VAMP7-dependent synaptic vesicle pool and selectively augments spontaneous neurotransmission

   Neuron 80:934–946.

   https://doi.org/10.1016/j.neuron.2013.08.024

   • PubMed
   • Google Scholar
3. 1. Beffert U
   2. Weeber EJ
   3. Durudas A
   4. Qiu S
   5. Masiulis I
   6. Sweatt JD
   7. Li WP
   8. Adelmann G
   9. Frotscher M
   10. Hammer RE
   11. Herz J

   (2005) Modulation of synaptic plasticity and memory by reelin involves differential splicing of the lipoprotein receptor Apoer2

   Neuron 47:567–579.

   https://doi.org/10.1016/j.neuron.2005.07.007

   • PubMed
   • Google Scholar
4. 1. Bell RD
   2. Winkler EA
   3. Singh I
   4. Sagare AP
   5. Deane R
   6. Wu Z
   7. Holtzman DM
   8. Betsholtz C
   9. Armulik A
   10. Sallstrom J
   11. Berk BC
   12. Zlokovic BV

   (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A

   Nature 485:512–516.

   https://doi.org/10.1038/nature11087

   • PubMed
   • Google Scholar
5. 1. Blacklow SC

   (2007) Versatility in ligand recognition by LDL receptor family proteins: advances and frontiers

   Current Opinion in Structural Biology 17:419–426.

   https://doi.org/10.1016/j.sbi.2007.08.017

   • PubMed
   • Google Scholar
6. 1. Brett CL
   2. Wei Y
   3. Donowitz M
   4. Rao R

   (2002) Human Na⁽⁺)/H⁽⁺) exchanger isoform 6 is found in recycling endosomes of cells, not in mitochondria

   American Journal of Physiology. Cell Physiology 282:C1031–C1041.

   https://doi.org/10.1152/ajpcell.00420.2001

   • PubMed
   • Google Scholar
7. 1. Campion D
   2. Dumanchin C
   3. Hannequin D
   4. Dubois B
   5. Belliard S
   6. Puel M
   7. Thomas-Anterion C
   8. Michon A
   9. Martin C
   10. Charbonnier F
   11. Raux G
   12. Camuzat A
   13. Penet C
   14. Mesnage V
   15. Martinez M
   16. Clerget-Darpoux F
   17. Brice A
   18. Frebourg T

   (1999) Early-onset autosomal dominant alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum

   The American Journal of Human Genetics 65:664–670.

   https://doi.org/10.1086/302553

   • PubMed
   • Google Scholar
8. 1. Casey JR
   2. Grinstein S
   3. Orlowski J

   (2010) Sensors and regulators of intracellular pH

   Nature Reviews Molecular Cell Biology 11:50–61.

   https://doi.org/10.1038/nrm2820

   • Google Scholar
9. 1. Castellano JM
   2. Kim J
   3. Stewart FR
   4. Jiang H
   5. DeMattos RB
   6. Patterson BW
   7. Fagan AM
   8. Morris JC
   9. Mawuenyega KG
   10. Cruchaga C
   11. Goate AM
   12. Bales KR
   13. Paul SM
   14. Bateman RJ
   15. Holtzman DM

   (2011) Human apoE isoforms differentially regulate brain amyloid-β peptide clearance

   Science Translational Medicine 3:89ra57.

   https://doi.org/10.1126/scitranslmed.3002156

   • PubMed
   • Google Scholar
10. 1. Cataldo AM
    2. Peterhoff CM
    3. Troncoso JC
    4. Gomez-Isla T
    5. Hyman BT
    6. Nixon RA

    (2000)

    Endocytic pathway abnormalities precede amyloid beta deposition in sporadic alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations

    The American Journal of Pathology 157:277–286.

    • PubMed
    • Google Scholar
11. 1. Chen L
    2. Chen CX
    3. Gan XT
    4. Beier N
    5. Scholz W
    6. Karmazyn M

    (2004) Inhibition and reversal of myocardial infarction-induced hypertrophy and heart failure by NHE-1 inhibition

    American Journal of Physiology-Heart and Circulatory Physiology 286:H381–H387.

    https://doi.org/10.1152/ajpheart.00602.2003

    • PubMed
    • Google Scholar
12. 1. Chen Y
    2. Beffert U
    3. Ertunc M
    4. Tang TS
    5. Kavalali ET
    6. Bezprozvanny I
    7. Herz J

    (2005) Reelin modulates NMDA receptor activity in cortical neurons

    Journal of Neuroscience 25:8209–8216.

    https://doi.org/10.1523/JNEUROSCI.1951-05.2005

    • PubMed
    • Google Scholar
13. 1. Chen Y
    2. Durakoglugil MS
    3. Xian X
    4. Herz J

    (2010) ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling

    PNAS 107:12011–12016.

    https://doi.org/10.1073/pnas.0914984107

    • PubMed
    • Google Scholar
14. 1. Choi HY
    2. Liu Y
    3. Tennert C
    4. Sugiura Y
    5. Karakatsani A
    6. Kröger S
    7. Johnson EB
    8. Hammer RE
    9. Lin W
    10. Herz J

    (2013) APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice

    eLife 2:e00220.

    https://doi.org/10.7554/eLife.00220

    • PubMed
    • Google Scholar
15. 1. Cirrito JR
    2. Kang JE
    3. Lee J
    4. Stewart FR
    5. Verges DK
    6. Silverio LM
    7. Bu G
    8. Mennerick S
    9. Holtzman DM

    (2008) Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo

    Neuron 58:42–51.

    https://doi.org/10.1016/j.neuron.2008.02.003

    • PubMed
    • Google Scholar
16. 1. Corder EH
    2. Saunders AM
    3. Strittmatter WJ
    4. Schmechel DE
    5. Gaskell PC
    6. Small GW
    7. Roses AD
    8. Haines JL
    9. Pericak-Vance MA

    (1993) Gene dose of apolipoprotein E type 4 allele and the risk of alzheimer's disease in late onset families

    Science 261:921–923.

    https://doi.org/10.1126/science.8346443

    • PubMed
    • Google Scholar
17. 1. D'Arcangelo G
    2. Miao GG
    3. Chen SC
    4. Soares HD
    5. Morgan JI
    6. Curran T

    (1995) A protein related to extracellular matrix proteins deleted in the mouse mutant reeler

    Nature 374:719–723.

    https://doi.org/10.1038/374719a0

    • PubMed
    • Google Scholar
18. 1. D'Arcangelo G
    2. Nakajima K
    3. Miyata T
    4. Ogawa M
    5. Mikoshiba K
    6. Curran T

    (1997) Reelin is a secreted glycoprotein recognized by the CR-50 monoclonal antibody

    The Journal of Neuroscience 17:23–31.

    https://doi.org/10.1523/JNEUROSCI.17-01-00023.1997

    • PubMed
    • Google Scholar
19. 1. Dean DC
    2. Jerskey BA
    3. Chen K
    4. Protas H
    5. Thiyyagura P
    6. Roontiva A
    7. O'Muircheartaigh J
    8. Dirks H
    9. Waskiewicz N
    10. Lehman K
    11. Siniard AL
    12. Turk MN
    13. Hua X
    14. Madsen SK
    15. Thompson PM
    16. Fleisher AS
    17. Huentelman MJ
    18. Deoni SC
    19. Reiman EM

    (2014) Brain differences in infants at differential genetic risk for late-onset alzheimer disease: a cross-sectional imaging study

    JAMA Neurology 71:11–22.

    https://doi.org/10.1001/jamaneurol.2013.4544

    • PubMed
    • Google Scholar
20. 1. Dean KM
    2. Roudot P
    3. Welf ES
    4. Pohlkamp T
    5. Garrelts G
    6. Herz J
    7. Fiolka R

    (2017) Imaging subcellular dynamics with fast and Light-Efficient volumetrically parallelized microscopy

    Optica 4:263–271.

    https://doi.org/10.1364/OPTICA.4.000263

    • PubMed
    • Google Scholar
21. 1. Decourt B
    2. Mobley W
    3. Reiman E
    4. Shah RJ
    5. Sabbagh MN

    (2013)

    Recent perspectives on APP, secretases, endosomal pathways and how they influence Alzheimer's Related Pathological Changes in Down Syndrome

    Journal of Alzheimer's Disease & Parkinsonism Suppl 7:002.

    • Google Scholar
22. 1. Del Río JA
    2. Heimrich B
    3. Borrell V
    4. Förster E
    5. Drakew A
    6. Alcántara S
    7. Nakajima K
    8. Miyata T
    9. Ogawa M
    10. Mikoshiba K
    11. Derer P
    12. Frotscher M
    13. Soriano E

    (1997) A role for Cajal-Retzius cells and reelin in the development of hippocampal connections

    Nature 385:70–74.

    https://doi.org/10.1038/385070a0

    • PubMed
    • Google Scholar
23. 1. Durakoglugil MS
    2. Chen Y
    3. White CL
    4. Kavalali ET
    5. Herz J

    (2009) Reelin signaling antagonizes beta-amyloid at the synapse

    PNAS 106:15938–15943.

    https://doi.org/10.1073/pnas.0908176106

    • PubMed
    • Google Scholar
24. 1. Fagan AM
    2. Watson M
    3. Parsadanian M
    4. Bales KR
    5. Paul SM
    6. Holtzman DM

    (2002) Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of alzheimer's disease

    Neurobiology of Disease 9:305–318.

    https://doi.org/10.1006/nbdi.2002.0483

    • PubMed
    • Google Scholar
25. 1. Förster E
    2. Kaltschmidt C
    3. Deng J
    4. Cremer H
    5. Deller T
    6. Frotscher M

    (1998)

    Lamina-specific cell adhesion on living slices of Hippocampus

    Development 125:3399–3410.

    • PubMed
    • Google Scholar
26. 1. Fuster DG
    2. Alexander RT

    (2014) Traditional and emerging roles for the SLC9 na+/H+ exchangers

    Pflügers Archiv - European Journal of Physiology 466:61–76.

    https://doi.org/10.1007/s00424-013-1408-8

    • Google Scholar
27. 1. Goldstein JL
    2. Brown MS
    3. Anderson RG
    4. Russell DW
    5. Schneider WJ

    (1985) Receptor-mediated endocytosis: concepts emerging from the LDL receptor system

    Annual Review of Cell Biology 1:1–39.

    https://doi.org/10.1146/annurev.cb.01.110185.000245

    • PubMed
    • Google Scholar
28. 1. Grassin-Delyle S
    2. Buenestado A
    3. Naline E
    4. Faisy C
    5. Blouquit-Laye S
    6. Couderc LJ
    7. Le Guen M
    8. Fischler M
    9. Devillier P

    (2012) Intranasal drug delivery: an efficient and non-invasive route for systemic administration: focus on opioids

    Pharmacology & Therapeutics 134:366–379.

    https://doi.org/10.1016/j.pharmthera.2012.03.003

    • PubMed
    • Google Scholar
29. 1. Harris JJ
    2. Jolivet R
    3. Attwell D

    (2012) Synaptic Energy Use and Supply

    Neuron 75:762–777.

    https://doi.org/10.1016/j.neuron.2012.08.019

    • Google Scholar
30. 1. Heeren J
    2. Grewal T
    3. Laatsch A
    4. Becker N
    5. Rinninger F
    6. Rye KA
    7. Beisiegel U

    (2004) Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation

    Journal of Biological Chemistry 279:55483–55492.

    https://doi.org/10.1074/jbc.M409324200

    • PubMed
    • Google Scholar
31. Book

    1. Herz j
    2. Xian X
    3. Yang Y

    (2010)

    Promoting Cycling of ApoE4 Isoform (USPTO)

    USA: University of Texas, Board of Regents.

    • Google Scholar
32. 1. Hiesberger T
    2. Trommsdorff M
    3. Howell BW
    4. Goffinet A
    5. Mumby MC
    6. Cooper JA
    7. Herz J

    (1999) Direct binding of reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation

    Neuron 24:481–489.

    https://doi.org/10.1016/S0896-6273(00)80861-2

    • PubMed
    • Google Scholar
33. 1. Howell BW
    2. Gertler FB
    3. Cooper JA

    (1997) Mouse disabled (mDab1): a src binding protein implicated in neuronal development

    The EMBO Journal 16:121–132.

    https://doi.org/10.1093/emboj/16.1.121

    • PubMed
    • Google Scholar
34. 1. Ishigaki Y
    2. Oikawa S
    3. Suzuki T
    4. Usui S
    5. Magoori K
    6. Kim DH
    7. Suzuki H
    8. Sasaki J
    9. Sasano H
    10. Okazaki M
    11. Toyota T
    12. Saito T
    13. Yamamoto TT

    (2000) Virus-mediated transduction of apolipoprotein E (ApoE)-sendai develops lipoprotein glomerulopathy in ApoE-deficient mice

    Journal of Biological Chemistry 275:31269–31273.

    https://doi.org/10.1074/jbc.M005906200

    • PubMed
    • Google Scholar
35. 1. Jonsson T
    2. Atwal JK
    3. Steinberg S
    4. Snaedal J
    5. Jonsson PV
    6. Bjornsson S
    7. Stefansson H
    8. Sulem P
    9. Gudbjartsson D
    10. Maloney J
    11. Hoyte K
    12. Gustafson A
    13. Liu Y
    14. Lu Y
    15. Bhangale T
    16. Graham RR
    17. Huttenlocher J
    18. Bjornsdottir G
    19. Andreassen OA
    20. Jönsson EG
    21. Palotie A
    22. Behrens TW
    23. Magnusson OT
    24. Kong A
    25. Thorsteinsdottir U
    26. Watts RJ
    27. Stefansson K

    (2012) A mutation in APP protects against Alzheimer's disease and age-related cognitive decline

    Nature 488:96–99.

    https://doi.org/10.1038/nature11283

    • PubMed
    • Google Scholar
36. 1. Karch CM
    2. Cruchaga C
    3. Goate AM

    (2014) Alzheimer's disease genetics: from the bench to the clinic

    Neuron 83:11–26.

    https://doi.org/10.1016/j.neuron.2014.05.041

    • PubMed
    • Google Scholar
37. 1. Kawasaki F
    2. Hazen M
    3. Ordway RW

    (2000) Fast synaptic fatigue in shibire mutants reveals a rapid requirement for dynamin in synaptic vesicle membrane trafficking

    Nature Neuroscience 3:859–860.

    https://doi.org/10.1038/78753

    • PubMed
    • Google Scholar
38. 1. Kim N
    2. Stiegler AL
    3. Cameron TO
    4. Hallock PT
    5. Gomez AM
    6. Huang JH
    7. Hubbard SR
    8. Dustin ML
    9. Burden SJ

    (2008) Lrp4 is a receptor for agrin and forms a complex with MuSK

    Cell 135:334–342.

    https://doi.org/10.1016/j.cell.2008.10.002

    • PubMed
    • Google Scholar
39. 1. Knouff C
    2. Hinsdale ME
    3. Mezdour H
    4. Altenburg MK
    5. Watanabe M
    6. Quarfordt SH
    7. Sullivan PM
    8. Maeda N

    (1999) Apo E structure determines VLDL clearance and atherosclerosis risk in mice

    Journal of Clinical Investigation 103:1579–1586.

    https://doi.org/10.1172/JCI6172

    • Google Scholar
40. 1. Kuchibhotla KV
    2. Goldman ST
    3. Lattarulo CR
    4. Wu HY
    5. Hyman BT
    6. Bacskai BJ

    (2008) Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks

    Neuron 59:214–225.

    https://doi.org/10.1016/j.neuron.2008.06.008

    • PubMed
    • Google Scholar
41. 1. Lane-Donovan C
    2. Philips GT
    3. Herz J

    (2014) More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration

    Neuron 83:771–787.

    https://doi.org/10.1016/j.neuron.2014.08.005

    • PubMed
    • Google Scholar
42. 1. Lane-Donovan C
    2. Herz J

    (2017) ApoE, ApoE receptors, and the synapse in Alzheimer's Disease

    Trends in Endocrinology & Metabolism 28:273–284.

    https://doi.org/10.1016/j.tem.2016.12.001

    • PubMed
    • Google Scholar
43. 1. Lin YT
    2. Seo J
    3. Gao F
    4. Feldman HM
    5. Wen HL
    6. Penney J
    7. Cam HP
    8. Gjoneska E
    9. Raja WK
    10. Cheng J
    11. Rueda R
    12. Kritskiy O
    13. Abdurrob F
    14. Peng Z
    15. Milo B
    16. Yu CJ
    17. Elmsaouri S
    18. Dey D
    19. Ko T
    20. Yankner BA
    21. Tsai LH

    (2018) APOE4 causes widespread molecular and cellular alterations associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types

    Neuron 98:1141–1154.

    https://doi.org/10.1016/j.neuron.2018.05.008

    • PubMed
    • Google Scholar
44. 1. Liu Q
    2. Zerbinatti CV
    3. Zhang J
    4. Hoe HS
    5. Wang B
    6. Cole SL
    7. Herz J
    8. Muglia L
    9. Bu G

    (2007) Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1

    Neuron 56:66–78.

    https://doi.org/10.1016/j.neuron.2007.08.008

    • PubMed
    • Google Scholar
45. 1. Liu Q
    2. Zhang J
    3. Zerbinatti C
    4. Zhan Y
    5. Kolber BJ
    6. Herz J
    7. Muglia LJ
    8. Bu G

    (2011) Lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis in the adult central nervous system

    PLoS Biology 9:e1000575.

    https://doi.org/10.1371/journal.pbio.1000575

    • PubMed
    • Google Scholar
46. 1. Liu CC
    2. Kanekiyo T
    3. Xu H
    4. Bu G

    (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

    Nature Reviews Neurology 9:106–118.

    https://doi.org/10.1038/nrneurol.2012.263

    • PubMed
    • Google Scholar
47. 1. Mahley RW

    (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology

    Science 240:622–630.

    https://doi.org/10.1126/science.3283935

    • PubMed
    • Google Scholar
48. 1. Masereel B
    2. Pochet L
    3. Laeckmann D

    (2003) An overview of inhibitors of na(+)/H(+) exchanger

    European Journal of Medicinal Chemistry 38:547–554.

    https://doi.org/10.1016/S0223-5234(03)00100-4

    • PubMed
    • Google Scholar
49. 1. May P
    2. Rohlmann A
    3. Bock HH
    4. Zurhove K
    5. Marth JD
    6. Schomburg ED
    7. Noebels JL
    8. Beffert U
    9. Sweatt JD
    10. Weeber EJ
    11. Herz J

    (2004) Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice

    Molecular and Cellular Biology 24:8872–8883.

    https://doi.org/10.1128/MCB.24.20.8872-8883.2004

    • PubMed
    • Google Scholar
50. 1. Moffat J
    2. Grueneberg DA
    3. Yang X
    4. Kim SY
    5. Kloepfer AM
    6. Hinkle G
    7. Piqani B
    8. Eisenhaure TM
    9. Luo B
    10. Grenier JK
    11. Carpenter AE
    12. Foo SY
    13. Stewart SA
    14. Stockwell BR
    15. Hacohen N
    16. Hahn WC
    17. Lander ES
    18. Sabatini DM
    19. Root DE

    (2006) A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen

    Cell 124:1283–1298.

    https://doi.org/10.1016/j.cell.2006.01.040

    • PubMed
    • Google Scholar
51. 1. Morrow JA
    2. Hatters DM
    3. Lu B
    4. Hochtl P
    5. Oberg KA
    6. Rupp B
    7. Weisgraber KH

    (2002) Apolipoprotein E4 forms a molten globule. A potential basis for its association with disease

    The Journal of Biological Chemistry 277:50380–50385.

    https://doi.org/10.1074/jbc.M204898200

    • PubMed
    • Google Scholar
52. 1. Nakajima C
    2. Kulik A
    3. Frotscher M
    4. Herz J
    5. Schäfer M
    6. Bock HH
    7. May P

    (2013) Low density lipoprotein receptor-related protein 1 (LRP1) modulates N-methyl-D-aspartate (NMDA) receptor-dependent intracellular signaling and NMDA-induced regulation of postsynaptic protein complexes

    Journal of Biological Chemistry 288:21909–21923.

    https://doi.org/10.1074/jbc.M112.444364

    • PubMed
    • Google Scholar
53. 1. Nixon RA
    2. Mathews PM
    3. Cataldo AM

    (2001) The neuronal endosomal-lysosomal system in Alzheimer's disease

    Journal of Alzheimer's Disease 3:97–107.

    https://doi.org/10.3233/JAD-2001-3114

    • PubMed
    • Google Scholar
54. 1. Ordovas JM
    2. Litwack-Klein L
    3. Wilson PW
    4. Schaefer MM
    5. Schaefer EJ

    (1987)

    Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms

    Journal of Lipid Research 28:371–380.

    • PubMed
    • Google Scholar
55. 1. Palop JJ
    2. Mucke L

    (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks

    Nature Neuroscience 13:812–818.

    https://doi.org/10.1038/nn.2583

    • PubMed
    • Google Scholar
56. 1. Pesold C
    2. Impagnatiello F
    3. Pisu MG
    4. Uzunov DP
    5. Costa E
    6. Guidotti A
    7. Caruncho HJ

    (1998) Reelin is preferentially expressed in neurons synthesizing gamma-aminobutyric acid in cortex and Hippocampus of adult rats

    PNAS 95:3221–3226.

    https://doi.org/10.1073/pnas.95.6.3221

    • PubMed
    • Google Scholar
57. 1. Pohlkamp T
    2. Dávid C
    3. Cauli B
    4. Gallopin T
    5. Bouché E
    6. Karagiannis A
    7. May P
    8. Herz J
    9. Frotscher M
    10. Staiger JF
    11. Bock HH

    (2014) Characterization and distribution of Reelin-positive interneuron subtypes in the rat barrel cortex

    Cerebral Cortex 24:3046–3058.

    https://doi.org/10.1093/cercor/bht161

    • PubMed
    • Google Scholar
58. 1. Pohlkamp T
    2. Durakoglugil M
    3. Lane-Donovan C
    4. Xian X
    5. Johnson EB
    6. Hammer RE
    7. Herz J

    (2015) Lrp4 domains differentially regulate limb/brain development and synaptic plasticity

    Plos One 10:e0116701.

    https://doi.org/10.1371/journal.pone.0116701

    • PubMed
    • Google Scholar
59. 1. Pohlkamp T
    2. Wasser CR
    3. Herz J

    (2017) Functional roles of the interaction of APP and lipoprotein receptors

    Frontiers in Molecular Neuroscience 10:54.

    https://doi.org/10.3389/fnmol.2017.00054

    • PubMed
    • Google Scholar
60. 1. Prasad H
    2. Rao R

    (2018) Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH

    PNAS 115:E6640–E6649.

    https://doi.org/10.1073/pnas.1801612115

    • PubMed
    • Google Scholar
61. 1. Rall SC
    2. Mahley RW

    (1992) The role of apolipoprotein E genetic variants in lipoprotein disorders

    Journal of Internal Medicine 231:653–659.

    https://doi.org/10.1111/j.1365-2796.1992.tb01254.x

    • Google Scholar
62. 1. Rellin L
    2. Heeren J
    3. Beisiegel U

    (2008) Recycling of apolipoprotein E is not associated with cholesterol efflux in neuronal cells

    Biochimica Et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1781:232–238.

    https://doi.org/10.1016/j.bbalip.2008.02.001

    • Google Scholar
63. 1. Robinson PJ
    2. Sontag J-M
    3. Liu J-P
    4. Fykse EM
    5. Slaughter C
    6. McMahontt H
    7. Südhof TC

    (1993) Dynamin GTPase regulated by protein kinase C phosphorylation in nerve terminals

    Nature 365:163–166.

    https://doi.org/10.1038/365163a0

    • Google Scholar
64. 1. Rönicke R
    2. Schröder UH
    3. Böhm K
    4. Reymann KG

    (2009) The Na+/H+ exchanger modulates long-term potentiation in rat hippocampal slices

    Naunyn-Schmiedeberg's Archives of Pharmacology 379:233–239.

    https://doi.org/10.1007/s00210-008-0364-x

    • Google Scholar
65. 1. Salehi A
    2. Delcroix JD
    3. Belichenko PV
    4. Zhan K
    5. Wu C
    6. Valletta JS
    7. Takimoto-Kimura R
    8. Kleschevnikov AM
    9. Sambamurti K
    10. Chung PP
    11. Xia W
    12. Villar A
    13. Campbell WA
    14. Kulnane LS
    15. Nixon RA
    16. Lamb BT
    17. Epstein CJ
    18. Stokin GB
    19. Goldstein LS
    20. Mobley WC

    (2006) Increased app expression in a mouse model of down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration

    Neuron 51:29–42.

    https://doi.org/10.1016/j.neuron.2006.05.022

    • PubMed
    • Google Scholar
66. 1. Selkoe DJ
    2. Hardy J

    (2016) The amyloid hypothesis of Alzheimer's disease at 25 years

    EMBO Molecular Medicine 8:595–608.

    https://doi.org/10.15252/emmm.201606210

    • PubMed
    • Google Scholar
67. 1. Shankar GM
    2. Li S
    3. Mehta TH
    4. Garcia-Munoz A
    5. Shepardson NE
    6. Smith I
    7. Brett FM
    8. Farrell MA
    9. Rowan MJ
    10. Lemere CA
    11. Regan CM
    12. Walsh DM
    13. Sabatini BL
    14. Selkoe DJ

    (2008) Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory

    Nature Medicine 14:837–842.

    https://doi.org/10.1038/nm1782

    • PubMed
    • Google Scholar
68. 1. Shankar GM
    2. Walsh DM

    (2009) Alzheimer's disease: synaptic dysfunction and Abeta

    Molecular Neurodegeneration 4:48.

    https://doi.org/10.1186/1750-1326-4-48

    • PubMed
    • Google Scholar
69. 1. Shaw P
    2. Lerch JP
    3. Pruessner JC
    4. Taylor KN
    5. Rose AB
    6. Greenstein D
    7. Clasen L
    8. Evans A
    9. Rapoport JL
    10. Giedd JN

    (2007) Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study

    The Lancet Neurology 6:494–500.

    https://doi.org/10.1016/S1474-4422(07)70106-0

    • PubMed
    • Google Scholar
70. 1. Sontag JM
    2. Fykse EM
    3. Ushkaryov Y
    4. Liu JP
    5. Robinson PJ
    6. Südhof TC

    (1994)

    Differential expression and regulation of multiple dynamins

    The Journal of Biological Chemistry 269:4547–4554.

    • PubMed
    • Google Scholar
71. 1. Strittmatter WJ
    2. Weisgraber KH
    3. Huang DY
    4. Dong LM
    5. Salvesen GS
    6. Pericak-Vance M
    7. Schmechel D
    8. Saunders AM
    9. Goldgaber D
    10. Roses AD

    (1993) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset alzheimer disease

    PNAS 90:8098–8102.

    https://doi.org/10.1073/pnas.90.17.8098

    • PubMed
    • Google Scholar
72. 1. Sudhof TC

    (2004) The synaptic vesicle cycle

    Annual Review of Neuroscience 27:509–547.

    https://doi.org/10.1146/annurev.neuro.26.041002.131412

    • PubMed
    • Google Scholar
73. 1. Sullivan PM
    2. Mezdour H
    3. Aratani Y
    4. Knouff C
    5. Najib J
    6. Reddick RL
    7. Quarfordt SH
    8. Maeda N

    (1997) Targeted replacement of the mouse apolipoprotein E gene with the common human APOE3 allele enhances diet-induced hypercholesterolemia and atherosclerosis

    Journal of Biological Chemistry 272:17972–17980.

    https://doi.org/10.1074/jbc.272.29.17972

    • PubMed
    • Google Scholar
74. 1. Townsend M
    2. Shankar GM
    3. Mehta T
    4. Walsh DM
    5. Selkoe DJ

    (2006) Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers

    The Journal of Physiology 572:477–492.

    https://doi.org/10.1113/jphysiol.2005.103754

    • PubMed
    • Google Scholar
75. 1. Trommsdorff M
    2. Gotthardt M
    3. Hiesberger T
    4. Shelton J
    5. Stockinger W
    6. Nimpf J
    7. Hammer RE
    8. Richardson JA
    9. Herz J

    (1999) Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2

    Cell 97:689–701.

    https://doi.org/10.1016/S0092-8674(00)80782-5

    • PubMed
    • Google Scholar
76. 1. Wasser CR
    2. Masiulis I
    3. Durakoglugil MS
    4. Lane-Donovan C
    5. Xian X
    6. Beffert U
    7. Agarwala A
    8. Hammer RE
    9. Herz J

    (2014) Differential splicing and glycosylation of Apoer2 alters synaptic plasticity and fear learning

    Science Signaling 7:ra113.

    https://doi.org/10.1126/scisignal.2005438

    • PubMed
    • Google Scholar
77. 1. Wasser CR
    2. Herz J

    (2017) Reelin: neurodevelopmental architect and homeostatic regulator of excitatory synapses

    Journal of Biological Chemistry 292:1330–1338.

    https://doi.org/10.1074/jbc.R116.766782

    • PubMed
    • Google Scholar
78. 1. Weeber EJ
    2. Beffert U
    3. Jones C
    4. Christian JM
    5. Forster E
    6. Sweatt JD
    7. Herz J

    (2002) Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning

    Journal of Biological Chemistry 277:39944–39952.

    https://doi.org/10.1074/jbc.M205147200

    • PubMed
    • Google Scholar
79. 1. Weisgraber KH

    (1994)

    Apolipoprotein E: structure-function relationships

    Advances in Protein Chemistry 45:249–302.

    • PubMed
    • Google Scholar
80. 1. Wildsmith KR
    2. Basak JM
    3. Patterson BW
    4. Pyatkivskyy Y
    5. Kim J
    6. Yarasheski KE
    7. Wang JX
    8. Mawuenyega KG
    9. Jiang H
    10. Parsadanian M
    11. Yoon H
    12. Kasten T
    13. Sigurdson WC
    14. Xiong C
    15. Goate A
    16. Holtzman DM
    17. Bateman RJ

    (2012) In vivo human apolipoprotein E isoform fractional turnover rates in the CNS

    PLoS ONE 7:e38013.

    https://doi.org/10.1371/journal.pone.0038013

    • PubMed
    • Google Scholar
81. 1. Wintersteiner O
    2. Abramson HA

    (1933)

    The isoelectric point of insulin: electrical properties of adsorbed and crystalline insulin

    The Journal of Biological Chemistry 99:741–753.

    • Google Scholar
82. 1. Zhang B
    2. Luo S
    3. Wang Q
    4. Suzuki T
    5. Xiong WC
    6. Mei L

    (2008) LRP4 serves as a coreceptor of agrin

    Neuron 60:285–297.

    https://doi.org/10.1016/j.neuron.2008.10.006

    • PubMed
    • Google Scholar
83. 1. Zhao N
    2. Liu CC
    3. Van Ingelgom AJ
    4. Martens YA
    5. Linares C
    6. Knight JA
    7. Painter MM
    8. Sullivan PM
    9. Bu G

    (2017) Apolipoprotein E4 impairs neuronal insulin signaling by trapping insulin receptor in the endosomes

    Neuron 96:115–129.

    https://doi.org/10.1016/j.neuron.2017.09.003

    • PubMed
    • Google Scholar

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

• 7,989

  views

• 1,132

  downloads

• 52

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.