Immunotherapy for Alzheimer's disease: rational basis in ongoing clinical trials

Amyloid-β (Aβ) immunotherapy has recently begun to gain considerable attention as a potentially promising therapeutic approach to reducing the levels of Aβ in the Central Nervous System (CNS) of patients with Alzheimer's Disease (AD). Despite extensive preclinical evidence showing that immunization with Aβ(1-42) peptide can prevent or reverse the development of the neuropathological hallmarks of AD, in 2002, the clinical trial of AN-1792, the first trial involving an AD vaccine, was discontinued at Phase II when a subset of patients immunized with Aβ(1-42) developed meningoencephalitis, thereby making it necessary to take a more refined and strategic approach towards developing novel Aβ immunotherapy strategies by first constructing a safe and effective vaccine. This review describes the rational basis in modern clinical trials that have been designed to overcome the many challenges and known hurdles inherent to the search for effective AD immunotherapies. The precise delimitation of the most appropriate targets for AD vaccination remains a major point of discussion and emphasizes the need to target antigens in proteins involved in the early steps of the amyloid cascade. Other obstacles that have been clearly defined include the need to avoid unwanted anti-Aβ/APP Th1 immune responses, the need to achieve adequate responses to vaccination in the elderly and the need for precise monitoring. Novel strategies have been implemented to overcome these problems including the use of N-terminal peptides as antigens, the development of DNA based epitope vaccines and vaccines based on passive immunotherapy, recruitment of patients at earlier stages with support of novel biomarkers, the use of new adjuvants, the use of foreign T cell epitopes and viral-like particles and adopting new efficacy endpoints. These strategies are currently being tested in over 10,000 patients enrolled in one of the more than 40 ongoing clinical trials, most of which are expected to report final results within two years.     

New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs

Current approved drug treatments for Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor antagonist memantine. These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop 'disease modifying drugs' hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD-related brain dysfunction, usable before clinical onset. Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy, with specific cut off values validated in clinical practice. Disease modifying drugs developed so far include drugs to reduce β amyloid (Aβ) production, drugs to prevent Aβ aggregation, drugs to promote Aβ clearance, drugs targeting tau phosphorylation and assembly and other approaches. Unfortunately none of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from methodological flaws to fundamental understanding of AD pathophysiology and biology. Recently, new diagnostic criteria applicable to presymptomatic stages of AD have been published. These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. Specific problems with completed trials and hopes with ongoing trials are discussed in this review.     

Immunotherapy for Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only Aβ has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen.     

Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia in North America. Growing evidence supports the concept that AD is fundamentally a metabolic disease that results in progressive impairment in the brain's capacity to utilize glucose and respond to insulin and insulin-like growth factor (IGF) stimulation. Moreover, the heterogeneous nature of AD is only partly explained by the brain's propensity to accumulate aberrantly processed, misfolded and aggregated oligomeric structural proteins, including amyloid-β peptides and hyperphosphorylated tau. Evidence suggests that other factors, including impaired energy metabolism, oxidative stress, neuroinflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into an overarching hypothesis to develop more realistic diagnostic and therapeutic approaches to AD. In this review, the interrelationship between impaired insulin and IGF signalling and amyloid-β pathology is discussed along with potential therapeutic approaches. Impairments in brain insulin/IGF signalling lead to increased expression of amyloid-β precursor protein (AβPP) and accumulation of AβPP-Aβ. In addition, they promote oxidative stress and deficits in energy metabolism, leading to the activation of pro-AβPP-Aβ-mediated neurodegeneration cascades. Although brain insulin/IGF resistance and deficiency can be induced by primary or secondary disease processes, the soaring rates of peripheral insulin resistance associated with obesity, diabetes mellitus and metabolic syndrome quite likely play major roles in the current AD epidemic. Both clinical and experimental data have linked chronic hyperinsulinaemia to cognitive impairment and neurodegeneration with increased AβPP-Aβ accumulation/reduced clearance in the CNS. Correspondingly, both the restoration of insulin responsiveness and the use of insulin therapy can lead to improved cognitive performance, although with variable effects on brain AβPP-Aβ load. On the other hand, experimental evidence supports the concept that the toxic effects of AβPP-Aβ can promote insulin resistance. Together, these findings suggest that a positive feedback loop of progressive neurodegeneration can develop whereby insulin resistance drives AβPP-Aβ accumulation, and AβPP-Aβ fibril toxicity drives brain insulin resistance. This phenomenon could explain why measuring AβPP-Aβ levels in cerebrospinal fluid or imaging of the brain has proven to be inadequate as a stand-alone biomarker for diagnosing AD, and why the clinical trial results of anti-AβPP-Aβ monotherapy have been disappointing. Instead, the aggregate data suggest that brain insulin resistance and deficiency must also be therapeutically targeted to halt AD progression or reverse its natural course. The positive therapeutic effects of different treatments that address the role of brain insulin/IGF resistance and deficiency, including the use of intranasal insulin delivery, incretins and insulin sensitizer agents are discussed along with potential benefits of lifestyle changes to modify risk for developing mild cognitive impairment or AD. Altogether, the data strongly support the notion that we must shift toward the implementation of multimodal rather than unimodal diagnostic and therapeutic strategies for AD.     

Alzheimer's disease & metals: therapeutic opportunities

Alzheimer's disease (AD) is the most common age related neurodegenerative disease. Currently, there are no disease modifying drugs, existing therapies only offer short-term symptomatic relief. Two of the pathognomonic indicators of AD are the presence of extracellular protein aggregates consisting primarily of the Aβ peptide and oxidative stress. Both of these phenomena can potentially be explained by the interactions of Aβ with metal ions. In addition, metal ions play a pivotal role in synaptic function and their homeostasis is tightly regulated. A breakdown in this metal homeostasis and the generation of toxic Aβ oligomers are likely to be responsible for the synaptic dysfunction associated with AD. Therefore, approaches that are designed to prevent Aβ metal interactions, inhibiting the formation of toxic Aβ species as well as restoring metal homeostasis may have potential as disease modifying strategies for treating AD. This review summarizes the physiological and pathological interactions that metal ions play in synaptic function with particular emphasis placed on interactions with Aβ. A variety of therapeutic strategies designed to address these pathological processes are also described. The most advanced of these strategies is the so-called 'metal protein attenuating compound' approach, with the lead molecule PBT2 having successfully completed early phase clinical trials. The success of these various strategies suggests that manipulating metal ion interactions offers multiple opportunities to develop disease modifying therapies for AD.     

Nuclear receptors as therapeutic targets for Alzheimer's disease

INTRODUCTION: Alzheimer's disease (AD) is characterized by the accumulation and extensive deposition of amyloid β (Aβ) in the parenchyma of the brain. This accumulation of amyloid is associated with perturbations in synaptic function, impairments in energy metabolism and induction of a chronic inflammatory response which acts to promote neuronal loss and cognitive impairment. AREAS COVERED: Currently, there are no drugs that target the underlying mechanisms of AD. Here, we propose a class of nuclear receptors as novel and promising new therapeutic targets for AD. This review summarizes the literature on nuclear receptors and their effects on AD-related pathophysiology. EXPERT OPINION: Nuclear receptors are attractive targets for the treatment of AD due to their ability to facilitate degradation of Aβ, affect microglial activation and suppress the inflammatory milieu of the brain. Liver X receptor agonists have proven difficult to move into clinical trials as long-term treatment results in hepatic steatosis. It is our view that PPAR-γ activation remains a promising avenue for the treatment for AD; however, the poor BBB permeability of the currently available agonists and the negative outcome of the Phase III clinical trials are likely to diminish interest in pursuing this target.     

Peptides for therapy and diagnosis of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with devastating effects. The greatest risk factor to develop AD is age. Today, only symptomatic therapies are available. Additionally, AD can be diagnosed with certainty only post mortem, whereas the diagnosis "probable AD" can be established earliest when severe clinical symptoms appear. Specific neuropathological changes like neurofibrillary tangles and amyloid plaques define AD. Amyloid plaques are mainly composed of the amyloid-βpeptide (Aβ). Several lines of evidence suggest that the progressive concentration and subsequent aggregation and accumulation of Aβ play a fundamental role in the disease progress. Therefore, substances which bind to Aβ and influence aggregation thereof are of great interest. An enormous number of organic substances for therapeutic purposes are described. This review focuses on peptides developed for diagnosis and therapy of AD and discusses the pre- and disadvantages of peptide drugs.     

Targeting ApoE4/ApoE receptor LRP1 in Alzheimer's disease

Introduction: Progressive neuronal loss is a key feature in Alzheimer's disease (AD), which is the most common neurodegenerative disorder in the aging population. Currently, there are no therapeutic means to intervene neuronal damage in AD and therefore innovative approaches to discover novel strategies for the treatment of AD are needed. Based on the prevailing amyloid cascade hypothesis, it is conceivable that lowering the β-amyloid (Aβ) levels is sufficient to slow down the disease process, if started early enough.

Areas covered: Here, we review genetic and biological functions related to apolipoprotein E (ApoE) and low-density lipoprotein receptor-related protein 1 receptor (LRP1)-mediated clearance of Aβ. Furthermore, we discuss the AD-related therapeutic potential of targeting to ApoE receptor LRP1 at the blood-brain barrier (BBB) and in the periphery.

Expert opinion: Due to the recent setbacks in the clinical trials targeting AD, it is instrumental to seek alternative therapeutic approaches, which aim to reduce the accumulation of Aβ in the brain tissue. As the ApoE/LRP1-mediated clearance of Aβ across the BBB is the key event in the regulation of Aβ transcytosis from brain to periphery, direct targeting of this protein entity at the BBB holds a great potential in the treatment of AD.     

Chlorzoxazone exhibits neuroprotection against Alzheimer’s disease by attenuating neuroinflammation and neurodegeneration in vitro and in vivo

Alzheimer’s disease (AD), a complex and an age-related brain disease, is induced by the accumulation of amyloid beta (Aβ) and neuroinflammation. Chlorzoxazone (CZ) is a classical FDA-approved drug, and shows anti-inflammatory effects. However, up until now, its regulatory role in AD has not been investigated. Therefore, in this study we attempted to explore if CZ could be an effective therapeutic strategy for AD treatment. At first, the in vitro study was performed to mimic AD using Aβ. We found that Aβ caused p65 nuclear translocation in both primary microglial cells and astrocytes, which were, however, restrained by CZ treatments. Meanwhile, CZ incubation markedly decreased the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β). Aβ deposition was also markedly reduced in glial cells treated with CZ. Importantly, we found that glial activation and its-related pro-inflammation induced by Aβ led to obvious neurodegeneration and neuroinflammation, which were effectively attenuated by CZ pre-treatment in the isolated primary cortical neurons. Then, the in vivo study was performed using APP/PS1 mice with AD. Behavior tests showed that CZ administration effectively improved cognitive deficits in AD mice. Neuron death in hippocampus of AD mice was also inhibited by CZ. Aβ accumulation in brain was markedly decreased in CZ-treated AD mice. We finally found that hippocampal glial activation in AD mice was obviously blocked by CZ supplementation, along with remarkable decreases in TNF-α, IL-1β and p65 nuclear translocation. Together, these findings above demonstrated that CZ could inhibit glial activation and inflammatory response, contributing to the suppression of neurodegeneration and neuroinflammation. Therefore, CZ may be an effective therapeutic strategy for AD treatment.     

Beta-secretase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Introduction: BACE 1 is a protease that cleaves the transmembrane amyloid precursor protein and generates amyloid-β peptides that accumulate in AD brains. No known mutations are identified in the gene encoding BACE1 in AD. However, enzyme levels are elevated in AD and a single residue mutation in amyloid precursor protein protects against protein cleavage by BACE1, suggesting BACE involvement in disease pathogenesis. Drugs that can inhibit BACE1 would theoretically prevent Aβ accumulation and halt AD onset and progression.

Areas covered: This review discusses clinical developments of BACE1 inhibitors and focuses on what is learned about these inhibitors as a potential treatment.

Expert opinion: BACE1 inhibition as a therapeutic strategy to improve cognition in AD has been challening. Brain-penetrant BACE1 inhibitors have been developed and clinical trials are underway, both safety and efficacy are questionable. Several clinical trials suggest that BACE1 inhibition and other immunotherapies to reduce brain Aβ are insufficient to improve cognition in AD. This may be due to the emphasis on the amyloid hypothesis despite big failures. We may have to seriously consider shifting attention to therapeutic strategies other than BACE1 inhibition or reduction of Aβ alone and pay more attention to simultaneous clearance of tau and Aβ.     

A survey of peptides with effective therapeutic potential in Alzheimer's disease rodent models or in human clinical studies

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia. Today, only palliative therapies are available. The pathological hallmarks of AD are the presence of neurofibrillary tangles and amyloid plaques, mainly composed of the amyloid-β peptide (Aβ), in the brains of the patients. Several lines of evidence suggest that the increased production and/or decreased cleavage of Aβ and subsequent accumulation of Aβ oligomers and aggregates play a fundamental role in the disease progress. Therefore, substances which bind to Aβ and influence aggregation thereof are of great interest. A wide range of Aβ binding peptides were investigated to date for therapeutic purposes. Only very few were shown to be effective in rodent AD models or in clinical studies. Here, we review those peptides and discuss their possible mechanisms of action.     

Beyond immunotherapy: new approaches for disease modifying treatments for early Alzheimer’s disease

Introduction: Current pharmacological recommendations for the treatment of Alzheimer’s disease (AD) include the cholinesterase inhibitors and the N-methyl-D-aspartate antagonist, memantine. However, these medications only manage symptoms of AD, and do not target Aβ plaques and neurofibrillary tangles. As such, there is a need to develop effective and safe disease modifying treatments that directly target AD pathology and alter the course of AD progression.

Areas covered: This review evaluates ongoing phase 2 and 3 clinical trials, as well as those completed or published over the past five years. Studies for this review were obtained from clinicaltrials.gov, alzforum.org/therapeutics, and PubMed. Keywords and search criteria included: phase 2, or 3 trials related to Alzheimer’s disease, mild cognitive impairment, amyloid-beta and tau. Immunotherapies for AD have not been included as this is beyond the scope of this review.

Expert opinion: A substantial number of trials investigating disease modifying drugs in AD target amyloid-beta and tau pathology. However, many of these trials have relatively short treatment duration and do not include combined assessment of biomarkers and clinical outcomes. Future investigations are recommended to include biomarker assessments and clinical outcomes over a minimum treatment duration of 18 months in order to establish disease-modifying effects.     

Mitochondrial dysfunction, apoptotic cell death, and Alzheimer's disease

Being major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and might therefore be particularly susceptible to oxidative injury. Mitochondrial damage may play a pivotal role in the cell death decision. Bolstered evidence indicates that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress occurring in Alzheimer’s disease (AD) finally contributing to synaptic failure and neuronal degeneration. Accumulation and oligomerization of amyloid beta (Aβ) is also thought to play a central role in the pathogenesis of this disease by probably directly leading to mitochondrial dysfunction. Moreover, numerous lines of findings indicate increased susceptibility to apoptotic cell death and increased oxidative damage as common features in neurons from sporadic AD patients but also from familial AD (FAD) cases. Here we provide a summary of recent work demonstrating some key abnormalities that may initiate and promote pathological events in AD. Finally, we emphasize a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, and Aβ production with mitochondrial dysfunction, caspase pathway, and neuronal loss.     

Novel aβ isoforms in Alzheimer's disease - their role in diagnosis and treatment

The last decades have witnessed an explosion in studies of the role of amyloid-β (Aβ) in the progress of the neurodegenerative disorder Alzheimer's disease (AD) and it is now widely accepted that Aβ is related to the pathogenesis of AD. For example, studies have shown that Aβ is neurotoxic and that the neurotoxicity of Aβ is related to its aggregation state. The concentration of the 42 amino acid form of Aβ (Aβ1-42) is reduced in the cerebrospinal fluid (CSF) from AD patients, which is believed to reflect the AD pathology with plaques in the brain acting as sinks. Less well investigated, however, is the ability of other Aβ isoforms to distinguish AD patients from controls and to identify treatment effects in clinical trials. Recently, novel C-truncated forms of Aβ (Aβ1-14, Aβ1-15, and Aβ1-16) were identified in human CSF. The presence of these small peptides is consistent with a catabolic amyloid precursor protein cleavage pathway by β- followed by α-secretase. It has been shown that Aβ1-14, Aβ1-15, and Aβ1-16 increase dose-dependently in response to γ-secretase inhibitor treatment while Aβ1-42 levels are unchanged. Here, we review the many aspects of Aβ and its isoforms with special focus on their potential role as diagnostic and theragnostic markers.     

A critical analysis of new molecular targets and strategies for drug developments in Alzheimer's disease

Alzheimer's disease (AD), a progressive, degenerative disorder of the brain, is believed to be the most common cause of dementia amongst the elderly. AD is characterized by the presence of amyloid deposits and neurofibrillary tangles in the brain of afflicted individuals. AD is associated with a loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning. AD appears to have a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in one of several genes, such as the beta-amyloid precursor protein (APP) and presenilins (PS1, PS2). These proteins along with tau, secretases, such as beta-amyloid cleaving enzyme (BACE), and apolipoprotein E play important roles in the pathology of AD. On therapeutic fronts, there is significant research underway in the development of new inhibitors for BACE, PS-1 and gamma-secretase as targets for treatment of AD. There is also a remarkable advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. The development of vaccination strategies, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy are examples of new approaches for treating or slowing the progression of AD. In addition, nutritional, genetic and environmental factors highlight more effective preventive strategies for AD. Developments of early diagnostic tools and of quantitative markers are critical to better follow the course of the disease and to evaluate different therapeutic strategies. In this review, we attempt to critically examine recent trends in AD research from molecular, genetic to clinical areas. We discuss various neurobiological mechanisms that provide the basis of new targets for AD drug development. All these current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain in order to effectively diagnose and prevent their occurrence.     

治疗阿尔采末病的药物靶点:β-分泌酶

近年来的研究表明,β-淀粉样蛋白(Aβ)是老年斑的主要成分,有明显的神经细胞毒性作用,在阿尔采末病(AD)的发病过程中发挥了重要作用,因此降低脑中Aβ的生成量是治疗AD的策略。Aβ是由β-和γ-分泌酶裂解其前体蛋白(APP)而生成,其中β-分泌酶(BACE)是启动Aβ形成的关键限速酶,因此BACE是开发治疗AD药物的一个具有吸引力的作用靶点。该文就近来对β-分泌酶的研究作一综述。     

Section Review Central & Peripheral Nervous Systems: Alzheimer's disease and β-amyloid: patent activity between May 1995 and July 1996

The patent literature describing activity relating to β-amyloid (Aβ) and Alzheimer's disease (AD) from May 1995 to July 1996 is reviewed. Inventions are classified into five groups: therapeutics that influence Aβ production, therapeutics based on interfering with Aβ aggregation and deposition, therapeutics based on interfering with Aβ neurotoxicity, diagnostics and animal models. While new chemical entities are described as therapeutic agents, the clinical development of these compounds is hindered by the lack of a widely available animal model which mimics the pathology of AD.     

An update on the efficacy of non-steroidal anti-inflammatory drugs in Alzheimer's disease

Several epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD), especially for patients carrying one or more ?4 allele of the apolipoprotein E. The biological mechanism of this protection is not completely understood and may involve inhibition of COX activity, inhibition of β-amyloid_1-42 (Aβ42) production and aggregation, inhibition of β-secretase activity, activation of PPAR-γ or stimulation of neurotrophin synthesis. Unfortunately, long-term, placebo-controlled clinical trials with both non-selective and COX-2 selective NSAIDs in AD patients produced negative results. A secondary prevention study with rofecoxib in patients with mild cognitive impairment and a primary prevention study with naproxen and celecoxib in elderly subjects with a family history of AD were also negative. All these failures have diminished the hope that NSAIDs could be beneficial in the treatment of AD. It is hypothesized that the chronic use of NSAIDs may be beneficial only in the normal brain by inhibiting the production of Aβ42. Once the Aβ deposition process has started, NSAIDs are no longer effective and may even be detrimental because of their inhibiting activity on activated microglia of the AD brain, which mediates Aβ clearance and activates compensatory hippocampal neurogenesis.     

Endothelin receptor antagonists: Potential in Alzheimer's disease

Alzheimer's disease (AD) is believed to be initiated by the accumulation of neurotoxic forms of Aβ peptide within the brain. AD patients show reduction of cerebral blood flow (CBF), the extent of the reduction correlating with the impairment of cognition. There is evidence that cerebral hypoperfusion precedes and may even trigger the onset of dementia in AD. Cerebral hypoperfusion impairs neuronal function, reduces the clearance of Aβ peptide and other toxic metabolites from the brain, and upregulates Aβ production. Studies in animal models of AD have shown the reduction in CBF to be more than would be expected for the reduction in neuronal metabolic activity. Aβ may contribute to the reduction in CBF in AD, as both Aβ_1–40 and Aβ_1–42 induce cerebrovascular dysfunction. Aβ_1–40 acts directly on cerebral arteries to cause cerebral smooth muscle cell contraction. Aβ_1–42 causes increased neuronal production and release of endothelin-1 (ET-1), a potent vasoconstrictor, and upregulation of endothelin-converting enzyme-2 (ECE-2), the enzyme which cleaves ET-1 from its inactive precursor. ET-1 and ECE-2 are also elevated in AD, making it likely that upregulation of the ECE-2–ET-1 axis by Aβ_1–42 contributes to the chronic reduction of CBF in AD. At present, only a few symptomatic treatment options exist for AD. The involvement of ET-1 in the pathogenesis of endothelial dysfunction associated with elevated Aβ indicates the potential for endothelin receptor antagonists in the treatment of AD. It has already been demonstrated that the endothelin receptor antagonist bosentan, preserves aortic and carotid endothelial function in Tg2576 mice, and our findings suggest that endothelin receptor antagonists may be beneficial in maintaining CBF in AD.