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.     

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.     

Alzheimer’s therapeutics

Factors limiting the therapeutic application of neurotrophins to neurodegenerative diseases include poor stability and CNS penetration. Moreover, certain neurotrophin effects, such as promotion of neuronal death via interaction with the p75NTR receptor, might further limit their application. We have proposed that development of small molecule mimetics of neurotrophins might serve to overcome these limitations. In previous work, our laboratory established the proof-of-principle that mimetics of specific nerve growth factor (NGF) domains could prevent neuronal death. Peptidomimetics of the loop 1 domain prevent death via p75NTR-dependent signaling and peptidomimetics of the loop 4 domain prevent death via Trk-related signaling. In current work we are designing pharmacophore queries corresponding to loop domains 1 or 4 that incorporate features of the NGF crystal structure along with features derived from peptidomimetic structure-activity-relationships. Screening of in silico databases containing non-peptide, small molecules has identified a number of candidate NGF domain mimetics. Preliminary assessment of these compounds using neurotrophin bioassays indicates that several are capable of preventing neuronal death. Ongoing studies will determine whether these compounds act via p75NTR or Trk receptors.     

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...     

Lingo-1：a novel target in therapy for Alzheimer’s disease?

正Unraveling the causes underlying Alzheimer’s disease(AD)is certainly one of the greatest challenges of this century for researchers.With advances in medicine and technology,the world is experiencing a demographic shift towards a growing elderly population.With this increasingly ageing population,the number of individuals being affected by AD is booming.AD has a significant negative impact on the lives of the individuals with the disorder,as well as creating a significant social and     

High thiamine diphosphate level as a protective factor for Alzheimer’s disease

Objectives Thiamine diphosphate (TDP) is an indispensable coenzyme for three key enzymes in glucose metabolism. Reduced TDP levels in patients with Alzheimer’s disease (AD) has been widely demonstrated and is a diagnostic biomarker for the disease. In this study, we further explored the correlation between altered TDP metabolism and AD along with other risk factors.

Methods A 1:1 case-control study was employed with 90 AD patients and 90 control subjects with normal-range cognitive abilities as assayed by the Mini Mental Status Evaluation. Age (≤2 years variation), gender, and educational background were strictly matched. Levels of the main thiamine metabolites in whole blood samples, including TDP, thiamine monophosphate, and thiamine, were assayed using high-performance liquid chromatography. Apolipoprotein E genotypes, haemoglobin, and several metabolic factors (fasting glucose, uric acid, triglyceride, and total cholesterol) associated with AD were also measured.

Results The odds ratio of TDP level for AD was 0.95 (with TDP level as a continuous variable) or 0.09 (with TDP level as a dichotomized variable with a cut-off value of 99.48 nmol/L). Blood TDP levels were significantly decreased in female AD patients compared to male AD patients. No correlations were identified between TDP levels and several metabolic factors (fasting glucose, uric acid, triglyceride, and total cholesterol).

Conclusions TDP is a protective factor for AD and its protective efficacy may be independent of other metabolic factors. The difference of TDP levels between genders may be another possible explanation for the higher prevalence of AD in females.     

Pharmacotheraphy for Alzheimer’s disease

In the past 2 years, substantive advances in therapy for Alzheimer’s disease (AD) have occurred. The nature of the effects of cholinesterase inhibitors has been refined with the publication of several studies that have examined different aspects of the symptomatology of AD. Break-throughs in the basic science of Alzheimer’s disease have led to new insights into potential therapeutic strategies targeted at the secretases involved in the metabolism of the Alzheimer precursor protein. An immunization approach, in which the β-amyloid protein itself was used as the immunizing agent, has also been presented and independently validated. Other areas of investigation with disappointing results, such as estrogen replacement therapy, anti-inflammatory approaches, and several other therapeutic agents, are also reviewed.     

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.     

Sigma-1 receptor：a potential new target for Parkinson’s disease？

<正>Parkinson’s disease(PD) is an age-related neurodegenerative disorder characterized by typical motor signs and symptoms that are due to dopamine(DA)depletion in the basal ganglia.The treatment of PD is symptomatic,and aims at replacing the lost DA input using either L-DOPA or DA agonists.The causes of PD are unknown in     

Apolipoprotein E genotype and progression of Alzheimer’s disease: the Rotterdam Study

The APOE*4 allele of the apolipoprotein E gene increases the risk of Alzheimer’s disease (AD), but whether it also affects the course of the disease is controversial. However, all studies on this issue until now have been based on patients at various stages of disease. In the present population-based study, 97 patients were included at a similar stage, i.e., before the onset of symptoms, and followed for up to 5 years. We found that the APOE*4 allele is not a strong determinant of survival in AD. As change in cognitive function and severity of dementia are similar for AD patients with and without APOE*4, our study suggests that progression of AD is not related to the APOE*4 allele. Received: 17 June 1998 Received in revised form: 8 September 1998 Accepted: 9 September 1998     

Astrocytes and therapeutics for Parkinson’s disease

Astrocytes play direct, active, and critical roles in mediating neuronal survival and function in various neurodegenerative disorders. This role of astrocytes is well illustrated in amyotrophic lateral sclerosis (ALS), in which the removal of glutamate from the extracellular space by astrocytes confers neuroprotection, whereas astrocytic release of soluble toxic molecules promotes neurodegeneration. In recent years, this context-dependent dual role of astrocytes has also been documented in experimental models of Parkinson’s disease. The present review addresses these studies and some potential mechanisms by which astrocytes may influence the neurodegenerative processes in Parkinson’s disease, and in particular examines how astrocytes confer neuroprotection either through the removal of toxic molecules from the extracellular space or through the release of trophic factors and antioxidant molecules. In contrast, under pathological conditions, astrocytes release proinflammatory cytokines and other toxic molecules that are detrimental to dopaminergic neurons. These emerging roles of astrocytes in the pathogenesis of Parkinson’s disease constitute an exciting development with promising novel therapeutic targets.     

Zona incerta as a therapeutic target in Parkinson’s disease

Journal of Neurology - The zona incerta has recently become an important target for deep-brain stimulation (DBS) in Parkinson’s disease (PD). The present review summarizes clinical, animal...     

Apolipoprotein ε4-Allele as a Significant Risk Factor for Conversion from Mild Cognitive Impairment to Alzheimer’s disease: a Meta-analysis of Prospective Studies

Recent studies of the relationship between progression from mild cognitive impairment (MCI) to Alzheimer disease (AD) and APOE ε4-allele revealed inconsistent results. To estimate the risk posed by APOE ε4-allele for developing AD in MCI subjects using meta-analysis and identify possible sources of heterogeneity between studies, we reviewed longitudinal epidemiological studies of the presence of APOE ε4-allele on risk for progression to dementia in MCI subjects, and conducted meta-analyses of the results from these studies. Our study was derived from 315 positive-outcome events and 461 negative-outcome events from 8 prospective studies. The pooled RR was statistically significant (pooled RR?=?2.09; 95 % CI, 1.52–2.88). The Q statistics indicated high heterogeneity across studies (Q?=?14.21, p?=?0.003). RR were significantly related to the ethnicity of the sample (z?=?3.58, p?=?0.024). No significant heterogeneity was observed after stratification in four European-population studies (χ ²?=?0.67, p?=?0.880), but it remained in four American-population studies (χ ²?=?18.52, p?=?0.003). Heterogeneity markedly reduced after excluding one specific study (Q?=?4.9, p?=?0.009; I ²?=?39 %). APOE ε4-allele conferred increased risk for progression to dementia in MCI subjects. Ethnicity is a critical factor to yield heterogeneity. Further studies using larger sample sizes are required.     

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.     

Apolipoprotein E dose-dependent modulation of β-amyloid deposition in a transgenic mouse model of Alzheimer’s disease

Susceptibility to the development of Alzheimer’s disease (AD) is increased for individuals harboring one or more apolipoprotein E4 (apoE4) alleles. Even though several isoform-specific effects of apoE have been identified, the relationship between biochemical function and risk factor assessment remains unknown. Our previous studies have demonstrated that there is an equilibrium between cerebral spinal fluid (CSF) and plasma β-amyloid (Aβ) and that amyloid plaques can modify this equilibrium. Trafficking of soluble central nervous system (CNS) Aβ is a very dynamic system that almost certainly is modulated by Aβ-binding proteins. Altered trafficking of the Aβ peptide might have a dramatic consequence as to whether the peptide is metabolized or begins to deposit within the brain. To gain a better understanding of the molecular mechanisms by which apoE influences AD pathogenesis and/or Aβ trafficking, we developed PDAPP transgenic mice that express different levels of human apoE3. Analysis of the soluble CNS pools of Aβ in young mice showed an apoE3 dose-dependent decrease in Aβ levels (E3^−/−>E3^−/−>E3^+/+). In addition to the dose-dependent effects on soluble Aβ, by 15 mo of age there were highly significant differences in the amount of deposited Aβ between the genotypes (E3^−/−>E3^−/−>E3^+/+). These data indicate that apoE3 provides a dose-dependent protective effect against Aβ deposition. This study suggests that increasing human apoE levels in brain might be a possible therapeutic target for preventing AD.     

Apolipoprotein E epsilon 4 is associated with an increased vulnerability to cell death in Alzheimer’s disease

Summary. The presumption to suffer from Alzheimer’s disease (AD) accelerates with aging. One important risk factor seems to be the isoform epsilon 4 of the apolipoprotein E gene (Apo ɛ4), which increases the risk to develop AD at an earlier age. Furthermore, convincing evidence is provided that apoptotic cell death mechanisms play an important role in neuronal cell death in AD. In the present study, we investigated whether abnormalities in apoptosis and caspase-3 activity can be found at the level of lymphocytes and a T cell subtype, CD4 T cells, from AD patients compared to aged sex- and ApoE genotype-matched non-demented controls. Under different experimental conditions (at baseline or after in vitro incubation in the presence of proapoptotic stimuli) increased levels of apoptosis and enhanced caspase-3 activity were detected in lymphocytes from AD patients. This difference was most pronounced in the CD4⁺ T cell subtype. Notably, we found a significant increase of apoptotic cells and caspase-3 activity in lymphocytes from AD patients bearing one or two alleles of the ApoE4 compared to non-E4 carriers. Again, these effects were strongest in CD4⁺ T cells. Circulating amyloid-beta (Aβ) levels did not differ between AD patients bearing ApoE4 and non-ApoE4 and age-matched controls. Therefore, it is likely that circulating Aβ is not responsible for the observed effects, which might rather reflect an ongoing systemic response in AD, e.g. an increase in CD95 expression.     

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.