TRANSCRIPTIONAL EFFECTS OF APOE4: RELEVANCE TO ALZHEIMER'S DISEASE
 
   

Transcriptional Effects of ApoE4:
Relevance to Alzheimer's Disease

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:     Frankp@chiro.org
 
   

FROM: Molecular Neurobiology 2018 (Jun); 55 (6): 5243–5254 ~ FULL TEXT

 Veena Theendakara & Clare A. Peters-Libeu & Dale E. Bredesen

The Buck Institute for Research on Aging,
8001 Redwood Blvd,
Novato, CA, 94945, USA.

Easton Laboratories for Neurodegenerative Disease Research,
UCLA, Los Angeles, CA, 90025, USA.

The major genetic risk factor for sporadic Alzheimer's disease (AD) is the lipid binding and transporting carrier protein apolipoprotein E, epsilon 4 allele (ApoE4). One of the unsolved mysteries of AD is how the presence of ApoE4 elicits this age-associated, currently incurable neurodegenerative disease. Recently, we showed that ApoE4 acts as a transcription factor and binds to the promoters of genes involved in a range of processes linked to aging and AD disease pathogenesis.

These findings point to novel therapeutic strategies for AD and aging, resulting in an extension of human healthspan, the disease-free and functional period of life. Here, we review the effects and implications of the putative transcriptional role of ApoE4 and propose a model of Alzheimer's disease that focuses on the transcriptional nature of ApoE4 and its downstream effects, with the aim that this knowledge will help to define the role ApoE4 plays as a risk factor for AD, aging, and other processes such as inflammation and cardiovascular disease.

Keywords:   Alzheimer’s disease; ApoE4; Apolipoprotein E; Neurodegeneration; Transcription


From the FULL TEXT Article:

Introduction

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder that affects over five million Americans, and at present, there are no pharmacological treatments known to cure or halt its progression. The biggest risk factor for AD is aging itself, but there are other determinants. One is a genetic variant termed APOE ε4, and interestingly, this variant is also linked to life span. However, the most common apolipoprotein E allele type is the APOE ε3, with a frequency range of 50– 90%, while APOE ε4 and APOE ε2 allele frequencies range from 5 to 35 and 1 to 5%, respectively. The risk for AD is associated with the APOE allele (ε4>ε3>ε2), and inheritance of one or two copies of APOE ε4 dramatically increases the late-onset AD risk approximately 3- or 12-fold, respectively [1, 2]. The protein structures of ApoE2, E3, and E4 are known. What has remained a mystery, however, is how subtle changes in the protein structure that distinguish the three isoforms lead to such profound changes in the risk and biology of AD.

Several genes, including Sirtuin1 (SirT1), have been linked to the normal aging process. Previous research from our group and from others discovered a link between apolipoprotein E, epsilon 4 allele (ApoE4) and SirT1, finding that most of the abnormalities associated with ApoE4 and AD in a cell culture model could be prevented by increasing the SirT1 activity [3]. These findings suggest that the activity of the SirT1 protein may be protective both against normal aging and AD. More recently, we provided new insights into the mechanism by which ApoE4 binds SirT1 and confers risk for AD [4], discovering that ApoE4 protein functions as a transcription factor, binding DNA and modulating the transcription of ~ 1700 genes, approximately half of which did not bind ApoE3. Notably, several of these genes have previously been linked to aging and AD pathogenesis and include genes involved in energy metabolism, inflammation, axon guidance, neuronal survival, and cell death [4]. Thus, it is noteworthy that the APOE ε4 allele is associated with aging and other agerelated diseases and that the associations between ApoE4, aging, and AD could be related mechanistically [5, 6].


ApoE4 and Neurodegeneration

The human ApoE protein is a 299 amino acid glycoprotein and is expressed in several organs, with the highest expression in the liver followed by the brain. ApoE is produced in abundance in the brain and serves as the principal lipid transport vehicle in CSF. In both human and rat brains, ApoE messenger RNA (mRNA) is abundant in the cerebral cortex, hippocampus, cerebellum, and medulla [7]. Non-neuronal cells, mainly astrocytes and microglia, are the major cell types that express ApoE in the brain [8–11]. Neurons can also produce ApoE under stressful conditions [7, 12].

ApoE functions as a ligand in receptor-mediated endocytosis of lipoprotein particles [13]. Unlike plasma HDL that contains ApoA-1 as its major apolipoprotein, the predominant apolipoprotein of HDL in the central nervous system (CNS) is ApoE [11]. Cholesterol released from ApoE-containing lipoprotein particles is used to support synaptogenesis and the maintenance of synaptic connections [14]. By the mid-1980s, several lines of evidence had been advanced that linked ApoE4 to neurodegeneration, including its role in AD, Parkinson’s disease (PD), cardiovascular diseases (CVD), multiple sclerosis (MS), type 2 diabetes mellitus (T2DM), vascular dementia (VD), and ischemic stroke (IS) [7, 15–17].

Several studies have shown a positive association between harboring the APOE ε4 allele and increased risk for VD [18–20], and a meta-analysis report has revealed evidence of an increased VD risk in individuals with ApoE4 compared with ApoE3 [19].

Similarly, epidemiologic studies have indicated a direct association between APOE and CVD as well as its impact on cholesterol levels [21]. In a study in middle-aged men, it was estimated that 40%of the ε4 carriers had an increased risk for CVD mortality compared with individuals with the APOE ε3/3 or ε2/2 genotypes [21–25], although other studies failed to find any association with ApoE4, and one study did show an increased CVD risk associated with the E2 allele [16, 25]. Thus, the exact role of ApoE in CVD remains enigmatic and needs to be explored further.

The study results of association of ApoE genotype with MS have been inconsistent [26, 27]. APOE ε4 allele may be a risk factor for cognitive impairment since patients with MS who possessed the E4 isoform were reported to present with verbal memory deficits [28–31].

While PD and AD have some overlapping clinical and neuropathological features, most studies have failed to report any association between ApoE4 genotype and susceptibility to PD or PD-associated dementia and studies focusing on the role of ApoE in PD have largely remained inconclusive [32–35].


ApoE and Alzheimer’s Disease

AD is a progressive, age-associated loss of cognitive function. Symptoms including memory losses typically appear after age 60, with some early-onset forms of the disease linked to a specific genetic defect. The disease is characterized by the presence of senile plaques and abnormal Tau tangles often starting in the hippocampal region. No cure exists for Alzheimer’s, and the drugs currently available to treat the disease address only its symptoms and with limited effectiveness. As the disease progresses, patients become totally dependent upon caregivers and eventually require comprehensive care. Thus, Alzheimer’s disease presents a considerable problem in patient management [36, 37]. One in eight older Americans has AD. An estimated 5.5 million Americans are living with Alzheimer’s dementia, although this number does not account for those individuals that are potential victims but not yet diagnosed with the disease. Thus, any therapeutic intervention that could postpone the onset or progression of AD would dramatically reduce the number of cases over the next 50 years [36, 37].

ApoE plays a critical role in transporting cholesterol in and out of the CNS and ApoE4 is the single most important genetic risk factor associated with AD. Individuals with two copies of the ApoE4 allele have an increased risk for sporadic or familial AD, with a significantly lower age of onset compared with AD patients not carrying this allele [7, 38–40]. Despite knowing for two decades that the ApoE4 allele is somehow contributory to the Alzheimer’s disease process, the precise molecular mechanisms underlying ApoE and β- amyloid precursor protein (APP) interactions, direct or indirect, resulting in ApoE4-mediated toxicity, remain unclear.


ApoE4 Effects on APP and AD Pathophysiology

The APP has been shown to function as a molecular switch: cleavage at the β, γ, and caspase sites results in the production of four pro-AD peptides—sAPPβ, Aβ, Jcasp, and C31—that mediate neurite retraction, synaptic reorganization, caspase activation, and ultimately programmed cell death. In contrast, cleavage at the α site produces the anti-AD trophic peptide sAPPα and the inhibitor of APP γ-site cleavage, α CTF [41]. The decision between these two proteolytic pathways is governed at least in part by ligand binding [41]. It has been shown that ApoE4 binds to APP with nanomolar affinity and decreases sAPPα secretion and reduces sAPPα/Aβ and sAPPα/sAPPβ ratios [3]. Furthermore, the level of CSF sAPPα is significantly lower in AD patients possessing one or two ApoE4 alleles than in those not possessing the ApoE4 allele [42]. In addition, treatment of human neuroblastoma cells with ApoE4 results in decreased secretion of sAPPα [43] and secretion of sAPPα is differentially affected by distinct ApoE isoforms as a functional consequence of the APPApoE interaction [44].

In addition to its effects on sAPPα reduction, several clinical studies have reported that cerebral Aβ deposition is positively associated with the ApoE4 genotype in cognitively normal subjects, mild cognitive impairment cases, and symptomatic AD patients [45–47], suggesting that ApoE4 may increase the risk of AD at least in part by initiating and accelerating Aβ accumulation, aggregation, and deposition in the brain [7, 38]. Data from several human studies confirm the ApoE genotype as a strong susceptibility factor for Aβ plaque accumulation and eventual development of AD [48, 49].

However, the mechanism by which ApoE4 directly promotes seeding and aggregation of Aβ in vivo remains unknown. Additionally, studies also suggest a role for ApoE4 in preventing Aβ clearance as a major pathogenic event for AD. Soluble Aβ can be removed from the brain by various clearance pathways. Lipidated ApoE can bind to Aβ (isoform-dependent with E3 >> E4) to form a ApoE–Aβ complex that is internalized by the cells through cell surface low density lipoprotein receptor-related protein 1 (LRP1) or lowdensity lipoprotein (LDL) receptors [48, 50]. While the endocytosed ApoE is recycled, Aβ is transported to the lysosomal compartment for degradation. Studies have shown that ApoE4 is less effective in promoting receptor-mediated Aβ clearance than ApoE3 [48, 51–54].

Furthermore, in the human brain, the macrophages have a critical role inAβ1–42 clearance and are extremely efficient at degrading soluble and insoluble Aβ that is also ApoE isoform dependent with E2 > E3 > E4 [55–57]. The ApoE-dependent, macrophage-induced Aβ degradation is blocked by the LDL receptor antagonist and receptor-associated protein (RAP) suggesting the involvement of one or more LDL receptors in mediating Aβ degradation and clearance by macrophages [56, 58]. ApoE4 may also prevent Aβ clearance by directly or indirectly blocking the activity of Aβ-degrading proteases including neprilysin (NEP), insulin-degrading enzyme (IDE), matrix metalloproteinases 2 and 9, and other proteases [59–65]. Hippocampal IDE protein is reduced by approximately 50% in AD patients with the ApoE4 genotype [63]. Studies also show that ApoE facilitates Aβ binding and lysosomal trafficking in an isoform-dependent manner, with ApoE3 more efficiently enhancing Aβ trafficking and degradation than ApoE4. ApoE3 enhances both the endolytic degradation of Aβ by NEP and extracellular Aβ degradation by IDE compared to ApoE4, although the mechanism remains unclear. Some studies have indicated the direct influence of ApoE4 in the regulation of IDE levels through the NMDA receptor pathway [64–66].


Other Effects of ApoE4 on AD Pathophysiology

Most of the APP and Aβ-independent effects of ApoE4 on AD pathophysiology have come from mouse models expressing human ApoE3 or ApoE4 that lack endogenous mouse ApoE [67]. Age and kainic acid-induced presynaptic and dendritic degeneration were exacerbated in NSE-ApoE4-Tg mice compared to NSE-ApoE3-Tg mice [68–70]. Furthermore, female NSE-ApoE4-Tg mice showed greater cognitive impairment compared to female NSE-ApoE3-Tg mice. ApoE4 is more susceptible to proteolytic cleavage than ApoE3 in vivo in these transgenic mouse models [68, 71–74]. The ApoE4 fragments accumulate in neurofibrillary tangles and amyloid plaques, disrupt cytoskeletal structure, and impair mitochondrial function [7, 68, 71, 73, 74]. Increased Tau phosphorylation is also observed in the ApoE4-Tg transgenic mice and in postmortem AD brains [3, 68, 73, 75, 76]. Morphological studies of these transgenic mouse lines demonstrate that human ApoE4 but not ApoE3 elicits neuronal and behavioral deficits in the absence of Aβ accumulation.

ApoE-TR mice were also developed to express each hApoE isoform (similar to the levels of ApoE isoforms in humans) and under the control of the endogenous mouse APOE promoter [67, 77–79]. ApoE4 levels were significantly lower in plasma, CSF, and brain homogenates than ApoE2 and ApoE3 [67]. The ApoE4-TR mice displayed decreased spine density and dendrite length, reduced excitatory transmission, and long-term potentiation compared to the ApoE3- TR mice. Female ApoE4-TR mice were cognitively impaired compared to female ApoE3-TR mice [78, 80]. ApoE4 and not ApoE3 inhibits neurite outgrowth, decreases dendritic spine density, and impairs adult hippocampal neurogenesis and neuronal plasticity in the different ApoE-Tg mouse models [7, 81–84].

Despite a wealth of data pointing to ApoE4’s manifold deleterious effects leading to AD pathophysiology, the mechanistic details of how ApoE4 causes all these effects leading to cellular toxicity remain incompletely defined. In addition, it is not clear if all of the previous effects stem from a direct interaction of ApoE4 with its target molecules or from an indirect mechanism.


ApoE4 Regulates Pathways Linking Aging and Alzheimer’s Disease

In addition to being a dominant risk factor for AD, the ApoE4 isoform is also linked to normal aging. We and others have shown that ApoE4 expression results in reduced expression and activity of Sirtuin1 (SirT1) in neural cells, ApoE4 TR mice, and AD postmortem tissue that featured at least one ApoE4 allele [3, 4, 85, 86]. SirT1, which belongs to the Sirtuin family of NAD-dependent protein deacetylases, has been linked to the normal aging process and also suppresses AD-related biochemical events in cells, primary neurons, and mouse models by directly activating transcription of ADAM10 and increasing the levels of the neuroprotective sAPPα [3, 4, 85, 87, 88].

SirT1 is interesting, since small molecules like resveratrol and other STACs (synthetic SIRT1 activating compounds) have been identified that activate this protein, which in model systems leads to life span extension, or improvements in healthspan [89–91]. Most of the abnormalities associated with ApoE4 and AD could also be prevented by increasing SirT1 activity [3, 4]. In addition to its effects on APP processing and signaling, ApoE4 and not ApoE3 triggered a marked reduction in the expression of SirT1 in cultured neural cells, cerebrospinal fluid, and in the brains of patients with AD [3, 4, 85, 86].

The ApoE4-mediated reduction in SirT1 mRNA levels correlated strongly with a reduction in SirT1 protein levels [3, 4]. Because SirT1 has been implicated in neuroprotection, this effect of ApoE4 may be important from both mechanistic and therapeutic development standpoints. It has been reported that SirT1 deficiency leads to hyperacetylation of Tau and accumulation of phosphorylated tau (p-Tau) and Aβ in mouse models of AD and in AD patients [92]. These findings suggest that increasing the SirT1 levels in an ApoE4 background may be protective both against normal aging and AD.


Indirect Transcriptional Role of ApoE

Several studies have now demonstrated an indirect role of ApoE4 in gene transcription. It has been demonstrated that the ApoE4 may act like a signaling molecule by increasing the nuclear translocation of histone deacetylases (HDACs) in human neurons that in turn reduce BDNF expression, in comparison to ApoE3, which increases histone-3 acetylation and upregulates BDNF expression. ApoE4 acts via LRP-1 receptors to modulate HDAC nucleo-cytoplasmic shuttling that is regulated by PKCε [93]. The exact mechanism underlying ApoE4 binding to LRP resulting in PKC activation, HDAC translocation to nucleus, and downregulation of BDNF expression remains unclear. In another recent study using human neurons derived from ES cells, Huang et al. showed that ApoE4 robustly stimulates APP transcription and Aβ production by activating a non-canonicalMAP kinase pathway involving DLK, MKK7, and ERK1/2. This cascade finally stimulates c-Fos phosphorylation and APP gene transcription, leading to increased APP and Aβ synthesis [94]. The factors that link the ApoE4 receptor complex to DLK activation remain unknown. In addition, it is not clear how APP transcription leads specifically to Aβ production without affecting the production of sAPPα or other related peptides.

In a report on the astrocyte transcriptome using astrocytes isolated from postmortem temporal cortex samples, Simpson et al. identified 237 genes that were differentially regulated by ApoE4. The 237 genes were categorized into six functional groups and included genes associated with signaling pathways, the cytoskeleton, DNA damage, metabolism, transcription, and the immune response [95]. While 164 genes were downregulated in ApoE4-associated astrocytes, the remainder of the genes was upregulated [95]. This differential regulation by ApoE4 could be a direct or indirect effect.

In another twist to its transcriptional role, Urfer et al. showed that the DNA sequence of the ApoE4 isoform itself controls the expression of other genes located in close proximity to the ApoE gene [96]. The ApoE4 DNA encompasses a de novo binding motif for the well-known transcription factor NRF1 whose targets include several neurodegenerative disease-related genes, such as PARK2, PINK1, PARK7, GPR37, PSENEN, and MAPK. The ApoE4/NRF1 complex offers a potential mechanism that links various triggers to an aberrant gene expression that influence the AD process. However, it is not clear from this study if the ApoE4/NRF1 DNA complex acts as a transcriptional activator, repressor, or both.


Direct Transcriptional Role of ApoE

One of the earliest reports indicating a transcriptional role of ApoE was reported by Zhang et al., when they described that ApoE selectively altered the type of steroid made by ovarian theca/interstitial cells by regulating the transcription of P450 17α-hydroxylase-C17–20 lyase mRNA [97]. Similarly, Levros et al. showed that ApoE constitutively bound to the apolipoprotein D (ApoD) promoter and repressed the ApoD promoter activity, thus demonstrating for the first time a transcriptional role for ApoE [98].

We too recently reported the transcriptional role of ApoE, first by showing that both ApoE3 and E4 bound to the Sirtuin1 (SirT1) promoter. Using several different procedures, we showed that ApoE4 and not ApoE3 significantly reduced SirT1 mRNA levels, SirT1 protein expression, and SirT1 enzyme activity [4]. Furthermore, we demonstrated that ApoE bound DNAwith high affinity (low nanomolar) in the promoter regions of over ~ 1700 genes. The genes associated with these promoters provided new insight into the mechanism by which AD risk is conferred by ApoE4, because they included genes associated with trophic support, programmed cell death, microtubule disassembly, synaptic function, aging, and insulin resistance, all processes that have been implicated in AD pathogenesis [4] (Figure 1).

While both ApoE3 and E4 regulate transcription, they have different outputs, with ApoE4 associated with promoters of genes linked to Alzheimer’s disease [4]. ApoE not only bound to the SirT1 promoter with high affinity but also repressed the promoter activity, suggesting a plausible role for ApoE4 in the nucleus as a transcriptional repressor in at least some settings. This conclusion was supported by the finding that four other genes—MADD, ADNP, COMMD6, and PPP2R5E (B56ε)— whose promoters also interacted with ApoE4, all showed reduced transcription in the presence of ApoE4 (and, to a lesser extent, in the presence of ApoE3) [4, 99]. There was a significant reduction in mRNA and protein levels of all four genes only in ApoE4-transfected cells compared with ApoE3- transfected cells or untransfected cells.

Immunohistochemical labeling of MADD, ADNP, and COMMD6 revealed greater expression of these proteins in the septal region of brains from 7-month-old ApoE3 TR mice compared with ApoE4 TR mice. MADD and COMMD6 regulate transcription by binding to the NFκB complex while ADNP functions as both an anti-apoptotic and anti-inflammatory gene [100–103]. Thus, the protein products of all three genes affect the inflammatory response, and, in each case, repression by ApoE4 would be expected to trigger inflammation and cell death, which is a hallmark of AD pathophysiology.

Protein phosphatase 2A (PP2A) is the principal tau dephosphorylating enzyme in the brain. Several abnormalities of PP2A have been reported in AD, including decreased protein levels of PP2A, decreased mRNA and protein levels of PP2AC and variable regulatory B subunits, and reduced methylation of PP2AC, all of which results in the reduction of the PP2A phosphatase activity [104–113]. Using a combination of human glioblastoma cells, ApoE3/4, and ApoE–/– NSC and human postmortem tissue, we showed that while both ApoE3 and E4 bound to the PPP2R5E promoter, only ApoE4 triggered a significant reduction in PP2A activity [99]. ApoE4 significantly repressed PPP2R5E mRNA levels and also reduced protein expression. Additionally, ApoE4 triggered demethylation of the PP2AC subunit of PP2A, resulting in the disruption of the PPP2R5E–PP2AC complex [99]. All of the previous PP2A modifications by ApoE4 provide an explanation for the reduction in PP2A activity in AD compared with ApoE3. This may also explain the elevated Tau phosphorylation in AD human brains featuring at least one ApoE4 allele.

Taking all these results together, the direct effects of ApoE4 on transcription of a small number of genes studied to date reveal only repressive effects; nevertheless, since we have not yet analyzed the interaction of ApoE with all of the gene promoters, we cannot fully substantiate the role of ApoE as a transcriptional repressor.


Nuclear Localization of ApoE4

If ApoE4 has a direct transcriptional role as mentioned previously, it indicates that it must enter the nucleus. The mechanism by which ApoE isoforms escape the secretory pathway and translocate to the cytosol or the nucleus is currently unclear. ApoE4 is known to trigger cellular stress including endoplasmic reticulum (ER) stress and cell death [3, 114, 115], and several reports have suggested that cellular and/or ER stress can result in mislocalization of proteins, resulting in their redistribution to the cytosol and nucleus [66, 116–121].

Similarly, several studies on the fate of misfolded protein clumps in the lysosomal/endosomal vesicles point to the escape of the cellular contents into the cytosolic compartment. According to these studies, misfolded protein clumps rupture intracellular vesicles following endocytosis allowing the proteins to then invade the cytoplasm and cause additional dysfunction [66, 120–122]. Interestingly, neurons fail to effectively degrade Aβ resulting in the formation of high molecular weight Aβ species in endosomal vesicles [123, 124] that could potentially rupture lysosomal/endosomal vesicles.

It has been established that ApoE accelerates neuronal Aβ uptake and lysosomal trafficking in an isoform-dependent manner with E3 >> E4 [66, 120, 121]. Any abnormalities or disturbance in the endocytoic pathway may result in the rupture of the endosomal vesicles causing the ApoE protein to accumulate in the cytosol [66, 120, 121, 125] (Fig. 1). From the cytosol, both full-length ApoE or fragments of ApoE isoforms could be transported into the nucleus by binding to specific nuclear proteins through their weak polybasic domains that may serve as nuclear signaling sequences (NLS) [98, 126–128]. Additionally, a subpopulation of ApoE on the cell surface may be a source of nuclear ApoE [119, 129] (Fig. 1). ApoE, which binds to the cell surface nucleolin may be transported to the nucleus as an ApoE–nucleolin complex similar to the transfer of cell surface midkine–nucleolin complex and other cell surface heparin binding proteins into the nucleus [119, 130–132].

The presence of ApoE in the nucleus has already been demonstrated in several cell types and tissues [98, 119, 127, 128, 133, 134] and may partly explain ApoE’s role as a transcription factor [4, 98]. Cancer cells are particularly prone to ER stress and mislocalization of proteins, with ER stress contributing to either survival or apoptosis of cancer cells depending on the setting [135]. Interestingly, several reports have described a positive correlation of cytosolic/nuclear ApoE immunoreactivity and clinical aggressiveness in prostate and ovarian cancers [134, 136].


Is ApoE an Authentic Transcription Factor?

Using the ChIP assay and SPR, we showed that both ApoE3 and ApoE4 bound to double-stranded DNAwith high affinity and that this binding required a specific region of DNA, present in the SirT1 promoter. Out of a total of 3080 promoter peaks examined, ~ 1700 were found to be associated with ApoE4 but not ApoE3 (Fig. 1). Because the kinetics of binding of ApoE3 or ApoE4 to DNAwere not significantly different, our data are consistent with the notion that the DNA binding site on ApoE is not influenced by either the sequence variation or the oligomerization state but by a different distribution of oligomers [4]. The genes associated with these promoters provided new insight into the mechanism by which AD risk is conferred by ApoE4, because they included genes associated with trophic support, programmed cell death, microtubule disassembly, synaptic function, aging, and insulin resistance, all processes that have been implicated in AD pathogenesis (Fig. 1). More specifically, ApoE not only bound to the SirT1 promoter with high affinity but also repressed its promoter activity, suggesting a plausible role for ApoE4 in the nucleus as a transcriptional repressor in at least some settings.

Thus, although the direct effects of ApoE4 on transcription of the small number of genes studied to date reveal only repressive effects, we cannot yet exclude the possibility that ApoE may in some cases turn out, with or without additional complex members, to function as a transcriptional activator. The estimated binding affinity of ApoE3 and ApoE4 (~ 10 nM) was in the range of known transcription factors [137, 138]. Both ApoE isoforms do not have high sequence similarity to the classical DNA binding proteins but do contain the helix–loop–helix secondary structure as well as high arginine content that is a characteristic of most DNA binding proteins [139, 140]. Binding of arginine residues to phosphate is very strong, and DNA-binding proteins use arginine to make critical interactions with the DNA backbone [141]. Because of its high arginine content, ApoE was originally named the arginine-rich protein [142], and these Arg residues might conceivably facilitate ApoE–DNA interaction.


Conclusions and Future Directions

It has been over two decades since the discovery that individuals carrying the ApoE4 allele are at increased risk for the development of AD in comparison to those possessing the ApoE3 or ApoE2 isoforms. Despite intensive research efforts that have revealed several important insights regarding ApoE4’s role in AD pathophysiology, a major unanswered question is the mechanism by which ApoE4 confers AD risk. Furthermore, not a single ApoE4-disease-modifying therapy has been approved for AD treatment thus far. Given that past failed clinical trials focused mostly on the same target — amyloid β-protein — it appears that targeting Aβ may not be enough to stop, reverse, or delay the disease. Genetic and biochemical research have revealed an extensive network of molecular interactions involved in AD pathogenesis, suggesting that a network-based therapeutics approach, rather than a single target-based approach, may be feasible and potentially more effective for the treatment of cognitive decline due to Alzheimer’s disease.

The fact that ApoE4 bound to a specific set of genes linked to the AD process suggests its increased vulnerability and as an AD risk factor. As discussed in the earlier sections, a relatively large body of literature now exists to support ApoE4’s roles in AD pathophysiology that are Aβ independent. The novel transcriptional role of ApoE4 needs more attention as it influences brain homeostasis beyond the known Aβ and Tau pathways [3, 4, 85]. The data supporting the transcriptional role of ApoE were mostly obtained using in vitro systems or using mouse models that are far from being physiological, although the effects were also observed in human AD brains. Indeed, human neuroblastoma and glioblastoma cells as well as human fibroblasts from AD patients do not reflect a system as complex as the human brain, and thus, as useful as the information obtained might be, it must be interpreted with caution. An essential next step in these studies is to determine whether the transcriptional effects of ApoE3 and ApoE4 are conserved in cells linked to AD, namely neurons and glial cells, especially when the proteins are expressed at endogenous levels. An attractive possibility to obtain a better understanding of ApoE’s transcriptional role in a physiological setting would be the use of isogenic iPSC-derived lineages expressing ApoE isoforms and exploring whether ApoE3/3 and ApoE4/4 neurons and glial cells differ transcriptionally from ApoE–/– controls.

Thus far, it appears that ApoE4, Tau and p-Tau, APP and p- APP, SirT1, PP2A, and inflammatory cytokines, including Il- 6 and Il-8, all may be part of a signaling network that is affected in AD [3–5, 57, 85], providing a high-throughput model for therapeutic candidate screening in AD drug discovery. Hence, this area needs much further exploration. Not discussed in this review is ApoE4’s additional role in triggering the immune response [4], which warrants further investigation.

In addition to ApoE4, the major risk factor for AD is aging itself, so future studies need to be directed at ApoE’s effects on specific cell populations (e.g., hippocampus and entorhinal cortex) in the brain as a consequence of aging itself. While most studies focus on animal models of AD, we need to be cautious about species differences between animals and humans in physiological function, lipid metabolism, the immune response, and cognition that might preclude mechanistic insights related to the disease. Human derived iPSCs and brain organoids would serve as the best models to complement the current animal models and pave the way toward a greater and clearer understanding of ApoE’s relationship with AD pathophysiology for effective therapies.

Acknowledgements

We thank the members of the DEB laboratory for helpful comments and discussions and Rowena Abulencia for administrative assistance. Our research work is supported in part by grants from the Buck-Impact Circle Funds (R.V.R), the Lucas Brothers Foundation (R.V.R), the Four Winds Foundation (D.E.B), the Marin Community Foundation (D.E.B), The John and Bonnie Strauss Foundation (R.V.R and D.E.B), and The Katherine Gehl Foundation (R.V.R and D.E.B).

Abbreviations

AD = Alzheimer’s disease
APP = β-amyloid precursor protein
ApoE = Apolipoprotein E
SirT1 = Sirtuin1
PP2A = Protein phosphatase 2A

Competing Interests

The authors declare that they have no competing interests.


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