Therapeutic implications of the prostaglandin pathway in Alzheimer's disease

An important pathologic hallmark of Alzheimer's disease (AD) is neuroinflammation, a process characterized in AD by disproportionate activation of cells (microglia and astrocytes, primarily) of the non-specific innate immune system within the CNS. While inflammation itself is not intrinsically detrimental, a delicate balance of pro- and anti-inflammatory signals must be maintained to ensure that long-term exaggerated responses do not damage the brain over time. Non-steroidal anti-inflammatory drugs (NSAIDs) represent a broad class of powerful therapeutics that temper inflammation by inhibiting cyclooxygenase-mediated signaling pathways including prostaglandins, which are the principal mediators of CNS neuroinflammation. While historically used to treat discrete or systemic inflammatory conditions, epidemiologic evidence suggests that protracted NSAID use may delay AD onset, as well as decrease disease severity and rate of progression. Unfortunately, clinical trials with NSAIDs have thus far yielded disappointing results, including premature discontinuation of a large-scale prevention trial due to unexpected cardiovascular side effects. Here we review the literature and make the argument that more targeted exploitation of downstream prostaglandin signaling pathways may offer significant therapeutic benefits for AD while minimizing adverse side effects. Directed strategies such as these may ultimately help to delay the deleterious consequences of brain aging and might someday lead to new therapies for AD and other chronic neurodegenerative diseases.     

Apolipoprotein E and Alzheimer's disease

Genetic variation in apolipoprotein E (APOE) influences Alzheimer's disease (AD) risk. APOE ε4 alleles are the strongest genetic risk factor for late onset sporadic AD. The AD risk is dose dependent, as those carrying one APOE ε4 allele have a 2–3-fold increased risk, while those carrying two ε4 alleles have a 10–15-fold increased risk. Individuals carrying APOE ε2 alleles have lower AD risk and those carrying APOE ε3 alleles have neutral risk. APOE is a lipoprotein which functions in lipid transport, metabolism, and inflammatory modulation. Isoform specific effects of APOE within the brain include alterations to Aβ, tau, neuroinflammation, and metabolism. Here we review the association of APOE with AD, the APOE isoform specific effects within brain and periphery, and potential therapeutics.     

Sex‐specific characterization and evaluation of the Alzheimer's disease genetic risk factor sorl1 in zebrafish during aging and in the adult brain following a 100 ppb embryonic lead exposure

Developmental lead (Pb) exposure is suggested in laboratory studies to be a trigger for neurodegenerative diseases such as Alzheimer's disease (AD). Sortilin‐related receptor, L (DLR class) A repeats‐containing (SORL1 ) is a recently identified AD genetic risk factor. SORL1 has limited characterization in vertebrate models in comparison to other AD genetic risk factors. To characterize SORL1 further, protein sequence homology between humans, mice and zebrafish was analyzed and showed conservation of functional repeats and domain orientation. Next, spatial expression of sorl1 in zebrafish larvae was completed and diffuse expression in neural tissue that was not restricted to the brain was observed. Influences of sex and age on quantitative expression of sorl1 in the brain of adult zebrafish were then assessed. Sex‐specific alteration of sorl1 expression transpired during the aging process in females. The zebrafish was then utilized to investigate the impacts of a 100 ppb embryonic Pb exposure on sorl1 expression and other known AD genetic risk factors. Sex‐specific quantitative gene expression analysis was completed with adult zebrafish brain to compare those developmentally exposed to Pb or a control treatment, but no significant difference in sorl1 expression or other AD genetic risk factors was observed. Overall, this study provided characterization of sorl1 with changes in brain expression during aging being female‐specific. This finding is in agreement with females being more prone to the onset of AD, but analysis of additional AD genetic risk factors is needed to facilitate our understanding of the impact of a 100 ppb embryonic Pb exposure. Copyright © 2016 John Wiley & Sons, Ltd.     

白藜芦醇治疗阿尔茨海默病的研究进展

神经退行性疾病是一种慢性进展性疾病,其特点是中枢神经系统神经元的逐渐丧失。由于血脑屏障的存在,经典的抗炎药物如类固醇激素和非甾体类抗炎药,对神经系统疾病的治疗作用有限。因此,开发新的抗炎药物,对于预防和治疗神经系统疾病具有重要的意义。白藜芦醇是一种有很强活性的天然多酚类物质,目前研究已显示其具有心血管保护、神经保护、免疫调节、肿瘤的化学预防作用。近年来还发现其具有抗神经炎症作用,可用于治疗神经精神性疾病,如帕金森病、阿尔茨海默病(AD)和亨廷顿症等。综述白藜芦醇对AD的保护作用及其机制研究进展,为进一步推进白藜芦醇用于防治AD的研究提供参考。     

Plasma inositol is not elevated in Alzheimer's disease

Brain inositol levels have been previously reported as elevated in Alzheimer's disease (AD) in brain. Brain inositol levels may be reflected in plasma levels. We therefore studied plasma inositol levels in 20 AD patients and 20 controls. Plasma inositol levels in the AD patients did not differ from values found in the controls. © 1998 John Wiley & Sons, Ltd.     

Safety and tolerability of transdermal and oral rivastigmine in Alzheimer's disease and Parkinson's disease dementia

Importance of the field: Cholinesterase inhibitors are the mainstay of symptomatic therapy for Alzheimer's disease (AD). Rivastigmine, an inhibitor of both acetylcholinesterase and butyrylcholinesterase, is available as a transdermal patch and in oral forms. It is also approved for the treatment of Parkinson's disease dementia (PDD) in many countries. The objective of this article is to review the safety and tolerability profile of transdermal and oral rivastigmine in AD and PDD patients.

Areas covered in this review: Articles were identified by searching MEDLINE in July 2009 using the terms rivastigmine, Exelon, ENA 713 and clinical trial. All double-blind, placebo-controlled randomized trials in which rivastigmine monotherapy was administered to AD or PDD patients for longer than 2 weeks were included.

What the reader will gain: This article provides a comprehensive summary of currently available safety data on rivastigmine.

Take home message: The main adverse events reported with rivastigmine therapy are gastrointestinal in nature. However, the transdermal patch appears to reduce these side effects, allowing more patients to access higher therapeutic doses. Overall, the safety profile of rivastigmine is favorable and the improved tolerability offered by the rivastigmine patch suggests that transdermal delivery may be the best way to deliver this drug in AD and PDD patients.     

Tau-aggregation inhibitor therapy for Alzheimer's disease

Many trials of drugs aimed at preventing or clearing β-amyloid pathology have failed to demonstrate efficacy in recent years and further trials continue with drugs aimed at the same targets and mechanisms.The Alzheimer neurofibrillary tangle is composed of tau and the core of its constituent filaments are made of a truncated fragment from the repeat domain of tau. This truncated tau can catalyse the conversion of normal soluble tau into aggregated oligomeric and fibrillar tau which, in turn, can spread to neighbouring neurons. Tau aggregation is not a late-life process and onset of Braak stage 1 peaks in people in their late 40s or early 50s. Tau aggregation pathology at Braak stage 1 or beyond affects 50% of the population over the age of 45.The initiation of tau aggregation requires its binding to a non-specific substrate to expose a high affinity tau–tau binding domain and it is self-propagating thereafter. The initiating substrate complex is most likely formed as a consequence of a progressive loss of endosomal–lysosomal processing of neuronal proteins, particularly of membrane proteins from mitochondria. Mutations in the APP/presenilin membrane complex may simply add to the age-related endosomal–lysosomal processing failure, bringing forward, but not directly causing, the tau aggregation cascade in carriers.Methylthioninium chloride (MTC), the first identified tau aggregation inhibitor (TAI), offers an alternative to the amyloid approach. Phase 3 trials are underway with a novel stabilized reduced form of methylthioninium (LMTX) that has improved tolerability and absorption.     

New and emerging treatments for Alzheimer's disease

Introduction: Alzheimer's disease and other dementias represent a significant and increasing clinical challenge. Dementia is also associated with a substantial economic cost and burden to health service provision. Existing treatments slow the progression of symptoms of the disease, but their efficacy does not extend to all patients and is not sustained beyond an average of 6 months. It is, therefore, critical to address the current lack of effective treatments to target the underlying pathology and disease process in Alzheimer's disease.

Areas covered: This review aims to highlight the main areas of new therapeutic development and discuss some of the main therapies currently being evaluated in clinical trials. Despite a number of promising rationales for therapeutic treatments in Alzheimer's disease, very few of these avenues have been developed beyond preclinical studies. The predominant focus of the current article is on treatments currently in Phase II and Phase III clinical trials, but some other promising areas of development are also discussed. There are currently only three therapeutics being investigated in Phase III clinical trials. This emphasizes the substantial caution and underinvestment in treatment development in this area.

Expert opinion: There is a distinct lack of novel approaches in the pipeline, and whether there is a new disease-modifying therapy for Alzheimer's disease in the next 5 years almost entirely depends on the success of currently ongoing immunotherapy studies. Importantly, there is potential benefit in exploring existing licensed treatments alongside novel drug development to increase the focus on novel targets within this time frame.     

Reasons that prevent the inclusion of Alzheimer's disease patients in clinical trials

Aim

To assess reasons that prevent Alzheimer''s disease (AD) patients from being included in clinical trials.

Methods

In 2009, we reviewed the Lille Memory Clinic''s case database to identify patients suitable for inclusion in four AD clinical trials. An initial selection was made on the basis of four criteria: (i) a diagnosis of AD (with or without white matter lesions [WML]), (ii) age, (iii) mini mental state examination (MMSE) score and (iv) symptomatic treatment of AD (cholinesterase inhibitors/memantine). Next, data on patients fulfilling these criteria were reviewed against all the inclusion/exclusion criteria for four clinical trials performed in 2009 at the Memory Clinic. Reasons for non-inclusion were analyzed.

Results

Two hundred and five patients were selected according to the four initial criteria. Reasons for subsequently not including some of patients in clinical trials were abnormalities on MRI (56.9%, 88.9% of which were WML), unauthorized medication (37.3%), the lack of a study partner/informant (37.1%), the presence of a non-authorized disease (24.4%), contraindication to MRI (9%), a change in diagnosis over time (3.9%), visual/auditory impairments (2.9%), alcohol abuse (2%) and an insufficient educational level (1%).

Conclusion

A high proportion of AD patients presented with vascular abnormalities on MRI. This was not unexpected, since the patients were selected from the database and, as shown in epidemiologic studies, cerebrovascular diseases are frequently associated with AD. The presence of a study partner is essential for enabling a patient to participate in clinical trials because of the need to record reliably primary and secondary outcomes.     

槲皮素对阿尔茨海默病的作用机制研究新进展

阿尔茨海默病是老年人最常见的神经退行性疾病,由于世界人口老龄化的加快,阿尔茨海默病的发病率随之持续增长,中药或中药提取物对神经保护作用的研究不断增多.槲皮素是一种黄酮类化合物,能够保护神经元免受氧化损伤,减少脂质过氧化,抑制淀粉样蛋白的原丝形成.本文对槲皮素的来源、药代动力学、对阿尔茨海默病的作用机制的新进展进行了综述...     

Neuropathological processes in Alzheimer's disease

During the past few years, substantial progress has been made in understanding the neuropathology of Alzheimer's disease (AD) and its late-life variant, senile dementia of the Alzheimer's type. Neurofibrillary tangles have been shown to be composed of cross-linked, highly insoluble paired helical filaments. The disease selectively affects certain populations of nerve cells, including those in the amygdala, hippocampus, neocortex, locus coeruleus and basal forebrain cholinergic (Ch) system. Changes in the latter system account, in substantial part, for the decrease in cortical Ch markers which, to date, appear to be the earliest and most consistent abnormalities in the brains of individuals with AD. Neuritic plaques have been shown to be foci of axonal/synaptic pathology consistent with the concept that these changes may be associated with a chronic distal axonopathy involving certain populations of nerve cells. Recent studies in aged nonhuman primates suggest that some of the abnormal axons/terminals in neuritic plaques may be derived from the basal forebrain Ch system. Understanding the biological mechanisms leading to these structural changes is essential if we are to understand the pathogenesis of the clinical manifestations of AD and if we are to design rational therapeutic approaches to treat this disorder.     

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

Diabetes mellitus (DM) is a gradually rising metabolic disease which is currently affecting millions of people worldwide. Diabetes is associated with various complications like nephropathy, neuropathy, retinopathy, diabetic foot, cognitive impairment, and many more. Evidence suggests that cognitive dysfunction is a rising complication of diabetes which adversely affects the brain of patients suffering from diabetes. Age-related memory impairment is a complication having its major effect on people suffering from diabetes and Alzheimer's. Patients suffering from diabetes are at two times higher risk of developing cognitive dysfunction as compared with normal individuals. Multiple factors which are involved in diabetes related complications are found to play a role in the development of neurodegeneration in Alzheimer's. The problem of insulin deficiency and insulin resistance is well reported in diabetes but there are many studies which suggest dysregulation of insulin levels as a reason behind the development of Alzheimer's. As the link between diabetes and Alzheimer disease (AD) is deepening, there is a need to understand the plausible tie-ins between the two. Emerging role of major factors like insulin imbalance, advanced glycation end products and micro-RNA's involved in diabetes and Alzheimer's have been discussed here. This review helps in understanding the plausible mechanism underlying the pathophysiology of amyloid beta (Aβ) plaque formation and tau hyperphosphorylation as well provides information about studies carried out in this area of research. The final thought is to enhance the scientific knowledge on this correlation and develop future therapeutics to treat the same.     

Rivastigmine: an update on therapeutic efficacy in Alzheimer's disease and other conditions

SUMMARY

The results of recent clinical trials with rivastigmine show that in the approved indication of mild to moderate Alzheimer's disease (AD), the drug is effective in the long term. Rivastigmine produces a significant delay in the decline of the three components of AD that have been identified by European guidelines as essential parameters for the assessment of therapeutic efficacy of medicinal products with this indication. These are cognitive function, the ability to perform the usual activities of daily living, and global judgement of the patient's condition by the patient himself, his caregiver and his doctor. Moreover, rivastigmine produces significant control of AD behavioural disorders. This further reduces caregiver burden, reduces the probability of institutionalisation, and enables the reduction or discontinuation of expensive and poorly tolerated antipsychotics. Recent trials also suggest that rivastigmine is effective in moderate to severe Alzheimer's disease, 'mixed' dementia (AD associated with vascular disorders) and Lewy body dementia. Preliminary investigations have also indicated that the drug may provide important benefits in patients with vascular dementia or dementia associated with Parkinson's disease. Pharmacoeconomic studies show that the therapeutic properties of rivastigmine result in economic savings for the care of demented patients living in the community.     

Nicotinic receptors and Alzheimer's disease

SUMMARY

Nicotinic receptors (NRs) belong to the group of polymeric receptors of the cell membrane and are key elements of cholinergic transmission. Numerous subtypes of NRs exist, with the α4β2 and α7 types being encountered most frequently. Deficiencies in NRs seem to play a role in Alzheimer's disease, which is characterised by accumulation of senile plaques, mainly composed of β-amyloid peptide (βA). Although the aetiology of this disease is unknown, different pathogenesis hypotheses implicating α7 NRs have been proposed, with the receptors exerting a direct or indirect action on the mechanism of βA toxicity. Allosteric modulators of NRs, such as the cholinesterase inhibitor galantamine, that facilitate the action of acetylcholine on these receptors may provide therapeutic benefits in the areas of cognition, attention and antineurodegenerative activity.     

Current perspectives on pharmacotherapy of Alzheimer's disease

Introduction: Alzheimer's disease (AD) is a daunting public health threat that has prompted the scientific community's ongoing efforts to decipher the underlying disease mechanism, and thereafter, target this therapeutically. Although basic research in AD has made remarkable progress over the past two decades, currently available drugs can only improve cognitive symptoms temporarily; no treatment can reverse, stop, or even slow this inexorable neurodegenerative process. Numerous disease-modifying strategies targeting the production and clearance of Aβ, as well as modulation of abnormal aggregation of tau filaments, are currently in clinical trials .

Areas covered: This review provides an overview of a wide array of therapeutic approaches under investigation, and the perspectives developed in the last 10 years.

Expert opinion: While it is not possible to predict the success of any individual program, one or more are likely to prove effective. Indeed, it seems reasonable to predict that in the not-too-distant future, a synergistic combination of agents will have the capacity to alter the neurodegenerative cascade and reduce the global impact of this devastating disease. The scientific community must acknowledge that Alzheimer's disease is a complex multifactorial disorder, and thus a single target or pathogenic pathway is unlikely to be identified. The major aim should be to design ligands with pluripotent pharmacological activities.