Apolipoprotein E4 as a target for developing new therapeutics for Alzheimer’s disease

The identification of factors that influence the onset or progression of the sporadic form of Alzheimer’s disease (AD) is a key step toward understanding its mechanism(s) and developing successful rational therapies. The apoE genotype has been identified as a powerful risk factor for AD that may account for as much as 50% of the sporadic form of the disease. As the major risk factor for late-onset AD, apolipoprotein E4 (apoE4) should be considered a good target for AD drug discovery. However, despite knowing for over a decade that apoE4 is detrimental to the disease process, we still remain uncertain about the molecular mechanisms subserving the risk-factor activity of apoE4. This, coupled with the fact that we know relatively little about the function(s) of apoE in brain, has presented a barrier to developing apoE-based therapeutics for AD. Progress has been made in understanding the neurobiology of apoE; a number of potentially overlapping functions have been ascribed, which include lipid transport, neuronal repair, dendritic growth, maintenance of synaptic plasticity, and anti-inflammatory activities. Until the gaps are filled in our understanding of the pathogenic function(s) of apoE4, therapeutic strategies targeting this protein will lag behind the development of other AD therapies. Putative pathological functions, or risk-factor activities, of apoE4 include its role in β-amyloid deposition, neurofibrillary tangle formation, synaptic loss, lipid dysfunction, neuroinflammation, and oxidative stress.     

Apolipoprotein E-related neurotoxicity as a therapeutic target for Alzheimer’s disease

Apolipoprotein E (apoE) remains the most important genetic risk factor for the development of Alzheimer's disease (AD). Still elusive, the role of apoE is under intense investigation. We propose that proteolysis of apoE in the brain leads to two major fragments, N- and C-terminal apoE, each of which would drive a different neuropathological pathway. N-terminal fragments of apoE are implicated in neurotoxicity, and C-terminal fragments might play a role in amyloid deposition and plaque formation. The greater risk of AD associated with the E4 isoform might relate to its greater neurotoxicity. Drugs that either directly inhibit the toxic effects of apoE or prevent the production of apoE fragments may provide novel therapeutic approaches to the treatment of AD and other disorders in which apoE is implicated.     

Apolipoprotein E,amyloid-beta,and neuroinflammation in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by the accumulation and deposition of amyloid-beta (Aβ) peptides in the brain. Neuroinflammation occurs in the AD brain and plays a critical role in the neurodegenerative pathology. Particularly, Aβ evokes an inflammatory response that leads to synaptic dysfunction, neuronal death, and neurodegeneration. Apolipoprotein E (ApoE) proteins are involved in cholesterol transport, Aβ binding and clearance, and synaptic functions in the brain. The ApoE4 isoform is a key risk factor for AD, while the ApoE2 isoform has a neuroprotective effect. However, studies have reached different conclusions about the roles of the isoforms; some show that both ApoE3 and ApoE4 have anti-inflammatory effects, while others show that ApoE4 causes a predisposition to inflammation or promotes an inflammatory response following lipopolysaccharide treatment. These discrepancies may result from the differences in models, cell types, experimental conditions, and inflammatory stimuli used. Further, little was known about the role of ApoE isoforms in the Aβ-induced inflammatory response and in the neuroinflammation of AD. Our recent work showed that ApoE isoforms differentially regulate and modify the Aβ-induced inflammatory response in neural cells, with ApoE2 suppressing and ApoE4 promoting the response. In this article, we review the roles, mechanisms, and interrelations among Aβ, ApoE, and neuroinflammation in AD.     

Apolipoprotein A1,the neglected relative of Apolipoprotein E and its potential role in Alzheimer’s disease

Lipoproteins are multi-molecule assemblies with the primary function of transportation and processing of lipophilic substances within aqueous bodily fluids(blood,cerebrospinal fluid).Nevertheless,they also exert other physiological functions such as immune regulation.In particular,neurons are both sensitive to uncontrolled responses of the immune system and highly dependent on a controlled and sufficient supply of lipids.For this reason,the role of certain lipoproteins and their protein-component(apolipoproteins,Apo’s)in neurological diseases is perceivable.ApoE,for example,is well-accepted as one of the major risk factors for sporadic Alzheimer’s disease with a protective allele variant(ε2)and a risk-causing allele variant(ε4).ApoA1,the major protein component of high-density lipoproteins,is responsible for transportation of excess cholesterol from peripheral tissues to the liver.The protein is synthesized in the liver and intestine but also can enter the brain via the choroid plexus and thereby might have an impact on brain lipid homeostasis.This review focuses on the role of ApoA1 in Alzheimer’s disease and discusses whether its role within this neurodegenerative disorder is specific or represents a general neuroprotective mechanism.     

Apolipoprotein E,amyloid-beta,and neuroinflammation in Alzheimer＇s disease

Alzheimer＇s disease （AD） is characterized by the accumulation and deposition of amyloid-beta （Aβ） peptides in the brain. Neuroinflammation occurs in the AD brain and plays a critical role in the neurodegenerative pathology. Particularly, Aβ evokes an inflammatory response that leads to synaptic dysfunction, neuronal death, and neurodegeneration. Apolipoprotein E （ApoE） proteins are involved in cholesterol transport, Aβ binding and clearance, and synaptic functions in the brain. The ApoE4 isoform is a key risk factor for AD, while the ApoE2 isoform has a neuroprotective effect. However, studies have reached different conclusions about the roles of the isoforms; some show that both ApoE3 and ApoE4 have anti-inflammatory effects, while others show that ApoE4 causes a predisposition to inflammation or promotes an inflammatory response following lipopolysaccharide treatment. These discrepancies may result from the differences in models, cell types, experimental conditions, and inflammatory stimuli used. Further, little was known about the role of ApoE isoforms in the Aβ-induced inflammatory response and in the neuroinflammation of AD. Our recent work showed that ApoE isoforms differentially regulate and modify the Aβ-induced inflammatory response in neural cells, with ApoE2 suppressing and ApoE4 promoting the response. In this article, we review the roles, mechanisms, and interrelations among Aβ, ApoE, and neuroinflammation in AD.     

Estimating the X chromosome-mediated risk for developing Alzheimer’s disease

Journal of Neurology - Parental lineage has been shown to increase the risk of Alzheimer’s disease (AD) in the offspring, with greater risk attributed to maternal lineage. While 40 genes/loci...     

Liposome based drug delivery as a potential treatment option for Alzheimer’s disease

Alzheimer’s disease is a neurodegenerative condition leading to atrophy of the brain and robbing nearly 5.8 million individuals in the United States age 65 and older of their cognitive functions.Alzheimer’s disease is associated with dementia and a progressive decline in memory,thinking,and social skills,eventually leading to a point that the individual can no longer perform daily activities independently.Currently available drugs on the market temporarily alleviate the symptoms,however,they are not successful in slowing down the progression of Alzheimer’s disease.Treatment and cures have been constricted due to the difficulty of drug delivery to the blood-brain barrier.Several studies have led to identification of vesicles to transport the necessary drugs through the blood-brain barrier that would typically not achieve the targeted area through systemic delivered medications.Recently,liposomes have emerged as a viable drug delivery agent to transport drugs that are not able to cross the blood-brain barrier.Liposomes are being used as a component of nanoparticle drug delivery;due to their biocompatible nature;and possessing the capability to carry both lipophilic and hydrophilic therapeutic agents across the blood brain barrier into the brain cells.Studies indicate the importance of liposomal based drug delivery in treatment of neurodegenerative disorders.The idea is to encapsulate the drugs inside the properly engineered liposome to generate a response of treatment.Liposomes are engineered to target specific diseased moieties and also several surface modifications of liposomes are under research to create a clinical path to the management of Alzheimer’s disease.This review deals with Alzheimer’s disease and emphasize on challenges associated with drug delivery to the brain,and how liposomal drug delivery can play an important role as a drug delivery method for the treatment of Alzheimer’s disease.This review also sheds some light on variation of liposomes.Additionally,it emphasizes on the liposomal formulations which are currently researched or used for treatment of Alzheimer’s disease and also discusses the future prospect of liposomal based drug delivery in Alzheimer’s disease.     

Prion protein gene M129 allele is a risk factor for Alzheimer’s disease

Summary. Prion protein gene polymorphism M129V represents a known risk factor for Creutzfeldt-Jakob disease. Recently, the meta-analysis revealed that homozygosity at codon 129 is connected with increased risk of Alzheimer’s disease (AD). To determine whether M129V polymorphism is a risk factor for AD we analyzed a group of early-onset, and late-onset Polish AD patients. We observed that in LOAD patients there is a statistically significant increase of MM (p = 0.0028) and decrease of MV (p = 0.0006) genotype frequency, as compared to controls. When both groups were stratified according to APOE4 status, increase of MM and decrease of MV genotype frequency were significant in the LOAD subgroup with no APOE4 (p = 0.017, and p = 0.018, respectively). In the subgroup with APOE4 allele, only MV genotype frequency was significantly lower, as com pared to controls (p = 0.035). However, no interaction was found between APOE4 status and M129V polymorphism. We conclude that MM genotype increases LOAD risk in Polish population independently from the APOE4 status.     

Apolipoprotein E,Receptors, and Modulation of Alzheimer’s Disease

Apolipoprotein E (apoE) is a lipid carrier in both the peripheral and the central nervous systems. Lipid-loaded apoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and injury repair in the brain. Considering prevalence and relative risk magnitude, the ε4 allele of the APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE4 contributes to AD pathogenesis by modulating multiple pathways, including but not limited to the metabolism, aggregation, and toxicity of amyloid-β peptide, tauopathy, synaptic plasticity, lipid transport, glucose metabolism, mitochondrial function, vascular integrity, and neuroinflammation. Emerging knowledge on apoE-related pathways in the pathophysiology of AD presents new opportunities for AD therapy. We describe the biochemical and biological features of apoE and apoE receptors in the central nervous system. We also discuss the evidence and mechanisms addressing differential effects of apoE isoforms and the role of apoE receptors in AD pathogenesis, with a particular emphasis on the clinical and preclinical studies related to amyloid-β pathology. Finally, we summarize the current strategies of AD therapy targeting apoE, and postulate that effective strategies require an apoE isoform–specific approach.     

Is X-linked methyl-CpG binding protein 2 a new target for the treatment of Parkinson’s disease？

X-linked methyl-CpG binding protein 2 mutations can induce symptoms similar to those of Parkinson’s disease and dopamine metabolism disorders, but the specific role of X-linked methyl-CpG binding protein 2 in the pathogenesis of Parkinson’s disease remains unknown. In the present study, we used 6-hydroxydopamine-induced human neuroblastoma cell （SH-SY5Y cells） injury as a cell model of Parkinson’s disease. The 6-hydroxydopamine （50 μmol/L） treatment decreased protein levels for both X-linked methyl-CpG binding protein 2 and tyrosine hydroxylase in these cells, and led to cell death. However, overexpression of X-linked methyl-CpG binding protein 2 was able to ameliorate the effects of 6-hydroxydopamine, it reduced 6-hydroxydopamine-induced apoptosis, and increased the levels of tyrosine hydroxylase in SH-SY5Y cells. These findings suggesting that X-linked methyl-CpG binding protein 2 may be a potential therapeutic target for the treatment of Parkinson’s disease.     

The Epigenome as a therapeutic target for Parkinson’s disease

Parkinsons disease(PD) is a common,progressive neurodegenerative disease characterised by degeneration of nigrostriatal dopaminergic neurons,aggregation of α-synuclein and motor symptoms.Current dopamine-replacement strategies provide symptomatic relief,however their effectiveness wear off over time and their prolonged use leads to disabling side-effects in PD patients.There is therefore a critical need to develop new drugs and drug targets to protect dopaminergic neurons and their axons from degeneration in PD.Over recent years,there has been robust evidence generated showing that epigenetic dysregulation occurs in PD patients,and that epigenetic modulation is a promising therapeutic approach for PD.This article first discusses the present evidence implicating global,and dopaminergic neuron-specific,alterations in the methylome in PD,and the therapeutic potential of pharmacologically targeting the methylome.It then focuses on another mechanism of epigenetic regulation,histone acetylation,and describes how the histone acetyltransferase(HAT) and histone deacetylase(HDAC) enzymes that mediate this process are attractive therapeutic targets for PD.It discusses the use of activators and/or inhibitors of HDACs and HATs in models of PD,and how these approaches for the selective modulation of histone acetylation elicit neuroprotective effects.Finally,it outlines the potential of employing small molecule epigenetic modulators as neuroprotective therapies for PD,and the future research that will be required to determine and realise this therapeutic potential.     

Apolipoprotein E is a prime suspect, not just an accomplice, in Alzheimer’s disease

There is now a large body of evidence suggesting that apolipoprotein E (apoE) genotype is the single most important genetic risk factor for the most common (sporadic) form of Alzheimer’s disease. Yet in proportion to the total number of investigations in this field, relatively few groups are studying the contribution of this cholesterol-binding protein to disease risk and severity. Of those that are, a major focus is on the impact of apoE on amyloid-related mechanisms of disease. I argue here that apoE should be considered a major culprit in its own right, not simply in a supporting role. The argument is based on several lines of evidence, including the fact that apoE is associated with both plaques and tangles, the overwhelming evidence for genetic risk of the disease attributed to apoE, increasing evidence that apoE might also modify risk of other nonamyloidogenic neurological diseases, neurotoxicity attributed to apoE and/or proteolytic fragments of apoE, negative consequences of transgenic expression of apoE4 in mice, and genetic evidence for polymorphisms that increase both apoE expression and disease risk, regardless of isoform.     

What is the new target inhibiting the progression of Alzheimer’s disease？

To stop the progression of Alzheimer＇s disease in the early stage, it is necessary to identify new therapeutic targets. We examined striatal-enriched phosphatase 61 expression in the brain tissues of 12-month-old APPswe/PSEN1dE9 transgenic mice. Immunohistochemistry showed that striatal-enriched phosphatase 61 protein expression was significantly increased but phosphorylated N-methyl-D-aspartate receptor 2B levels were significantly decreased in the cortex and hippocampus of APPswe/PSEN1dE9 transgenic mice. Western blotting of a cell model of Alzheimer＇s disease consisting of amyloid-beta peptide （1-42）-treated C57BL/6 mouse cortical neurons in vitro showed that valeric acid （AP5）, an N-methyl-D-aspartate receptor antagonist, significantly inhibited amyloidbeta 1-42-induced increased activity of striatal-enriched phosphatase 61. In addition, the phosphorylation of N-methyl-D-aspartate receptor 2B at Tyr1472 was impaired in amyloid-beta 1-42-treated cortical neurons, but knockdown of striatal-enriched phosphatase 61 enhanced the phosphorylation of N-methyl-D-aspartate receptor 2B. Collectively, these findings indicate that striatal-enriched phosphatase 61 can disturb N-methyl-D-aspartate receptor transport and inhibit the progression of learning and study disturbances induced by Alzheimer＇s disease. Thus, striatal-enriched phosphatase 61 may represent a new target for inhibiting the progression of Alzheimer＇s disease.     

Globodera pallida,a non-transgenic invertebrate as a new model for investigating Alzheimer’s disease(and other proteinopathies)?

Biological models of Alzheimer’s disease(AD):Non-human models have contributed tremendously to the understanding of AD and its underlying pathological processes.These models have aided the investigation of the genetic and environmental risk factors.They also have enabled the progression of candidate therapies into human clinical trials.Because of similarities with human brain anatomy and genetics,rodent models have been used extensively to recapitulate some aspects of AD pathology,measure AD-associated behavioral parameters and related nervous system dysfunctions(Eriksen and Janus,2007).For instance,transgenic mice overexpressing human amyloid precursor protein have furthered the development of the amyloid cascade hypothesis as a central pillar of familial AD.     

Clinical and research value of the new diagnostic criteria for Alzheimer’s disease

概述

在阿尔茨海默氏病（Alzheimer’s disease, AD）的诊断中采用生物标志物已日益得到重视，但在临床实践中使用生物标志物的可行性和价值仍然是有限的。然而，AD临床和制药研究中生物标志物的使用也许可以证明对明确AD的病理基础是非常有用的，并有助于提高在有效预防和治疗措施下的早期识别。此外，新诊断标准的广泛采用将提高不同研究结果之间的可比性，并为使用meta分析方法合并和比较不同研究的结果创造了可能性——这种分析能够明确回答关于AD的病因、病程、预防和治疗等基本问题。

中文全文

本文全文中文版从2015年6月6日起在http://dx.doi.org/10.11919/j.issn.1002-0829.215046可供免费阅览下载As discussed in the Forum article by Yang and Xiao, [1] in recent years there has been an increasing emphasis on the role of biomarkers in the diagnosis of Alzheimer’s disease (AD). Nonetheless, there are several potential serious problems in the clinical application of biomarkerbased diagnostic criteria for AD: a) The reliability of the biomarkers is not proven. Currently, there is a lack of consensus on the cutoff points that provide satisfactory sensitivity and specificity of the proposed biomarkers that would best distinguish ‘normal’ from ‘abnormal’. More clinical studies are needed to unify and standardize the proposed cutoffs points. For instance, amyloidbeta (Aβ) accumulation is also detected in healthy individuals, [2] and the specificity of identifying AD using cerebrospinal fluid (CSF) Aβ₄₂ and CSF tau varies from 49% to 77%. [3] At present the diagnosis of AD cannot rely solely on such biomarkers. b) The feasibility of assessing biomarkers is limited in clinical settings. The lack of an ideal tracer for PET and differences in Aβ and tau standards at different research institutes limits the broad application of these techniques. More importantly, the use of the tests for biomarkers is limited to locations that have the advanced (and expensive) equipment needed to make the assessments and the highly trained technicians who can operate and maintain the equipment and interpret the results. In low- or middle-income countries, these facilities are only available in prestigious health centers in large urban areas. Additional limitations may occur in countries where cultural factors c) There are ethical concerns about the early diagnosis of AD.The new diagnostic criteria stress the importance of early detection and propose the concept of a prodromal phase of AD. Some scholars suggest that the early detection of AD using biomarkers is little different from identifying carcinoma in situ (CIS) or using laboratory tests to identify prodromal phases of type-II diabetes, hypertension, renal insufficiency, and osteoporosis. However, the situation with AD is different because there is, as yet, little evidence that early detection and treatment of high-risk individuals (i.e., individuals with mild cognitive impairment) has any beneficial effects. [4,5] Furthermore, the psychological burden that is experienced by the individual and the individual’s family when an early diagnosis is made by a treating clinician can be as great as that caused by the disease itself. [6] Thus, there are serious ethical issues related to the early diagnosis of AD that are more prominent than those related to the early diagnosis of other conditions for which effective treatments are already available. d) The theoretical foundation of the new diagnostic criteria is inadequate.The new diagnostic criteria are completely based on theories about disturbed metabolism of Aβ and the resultant accumulation of Aβ. But this is only one of many etiological mechanisms that result in AD, so the markers only identify a subset of cases. Moreover, the proposed biomarkers are not pathognomonic, some individuals with these markers never develop AD. Despite these problems, it is undeniable that the emphasis on biomarkers in the new diagnostic criteria is an improvement. Studies on biomarkers have demonstrated that the conventional symptomologybased diagnostic criteria of AD can delay treatment because clinical symptoms greatly lag behind the actual onset of the disease. This delayed diagnosis delays both the clinical treatment of affected individuals and the development of new medications of other interventions to prevent or treat AD. Despite the uncertainty of their use in clinical practice, adopting biomarkers in clinical research and pharmaceutical studies can help distinguish AD from other types of dementia, advance our understanding of the pathology of AD, promote the initiation of interventions and treatments earlier in the course of the condition, improve the quality of the evaluation of effectiveness, and, thus, help in the development of new drugs and other treatments. A search on Web of Science found that many researchers are already publishing results based on these new diagnostic criteria. As of 5 April 2015 there have been 1059 articles published using the NINCDSADRDA criteria, 864 articles published using the NIAAA criteria, and 21 articles published using the IWG-2 criteria. The widespread use of these new diagnostic criteria in research studies can help homogenize the selection of samples and, thus, greatly improve the comparability of the studies. It would then be feasible to combine such studies in meta-analysis with large pooled samples, the type of comprehensive analyses that will be needed to provide clear answers to many of the perplexing issues that need to be resolved before it will be possible to identify effective interventions for this disabling condition. Additional work in the future will be needed to identify a subset of relatively easy to identity biomarkers that can be used in routine clinical care, particularly in low-resource settings in low- and middleincome countries.     

Insulin-degrading enzyme, apolipoprotein E, and Alzheimer’s disease

Insulin-degrading enzyme (IDE) is a protease that degrades insulin and the beta-amyloid (Abeta) peptide implicated in Alzheimer's disease (AD). Hence, factors that influence IDE expression or IDE activity toward Abeta are potentially relevant to the etiology of AD. Hippocampal IDE mRNA levels are lower on average in subjects with an APOE epsilon4 allele, suggesting that the genetic risk conferred by APOE epsilon4 may be mediated in part by this allele's effect on IDE expression. Other factors that influence IDE may be relevant in non-epsilon4 carriers. For example, insulin, a competitive inhibitor of IDE activity toward Abeta, may be elevated in non-epsilon4 cases. We here report IDE gene promoter region variants that are associated with AD in subjects without an epsilon4 allele. If these promoter region variants prove to affect expression levels, they may be relevant to disease as well. Further investigation of the relationship between APOE genotype, IDE genetic variants, and the expression and activity of hippocampal IDE is warranted.     

The cholesteryl ester transfer protein (CETP) gene and the risk of Alzheimer’s disease

Like the apolipoprotein E (APOE) gene, the most common genetic determinant for Alzheimer’s disease (AD), the cholesteryl ester transfer protein (CETP) is involved in lipid metabolism. We studied the I405V polymorphism of the CETP gene in relation to AD. We genotyped 544 AD cases and 5,404 controls from the Rotterdam study, using a TaqMan allelic discrimination assay. Odds ratios (ORs) for AD were estimated using logistic regression analysis. CETP VV carriers showed significantly increased high-density lipoprotein levels compared to the IV and II carriers. In the overall analysis of AD, the risk of disease for the VV carriers of the CETP polymorphism was non-significantly increased compared to II carriers OR_VV = 1.33, 95% confidence interval (CI) 0.96–1.90 p = 0.08). In those without the APOE*4 allele, the risk of AD for VV carriers was increased 1.67-fold (95% CI 1.11–2.52, p = 0.01). The difference in the relationship between CETP and AD between APOE*4 carriers and APOE*4 non-carriers was statistically significant (p for interaction = 0.04). Our results suggest that the VV genotype of the I405V polymorphism of the CETP gene increases the risk of AD in the absence of the APOE*4 allele, probably through a cholesterol metabolism pathway in the brain.