Elevation of BACE in an Aβ rat model of Alzheimer's disease: exacerbation by chronic stress and prevention by nicotine

In Alzheimer's disease (AD), progressive accumulation of β-amyloid (Aβ) peptides impairs nicotinic acetylcholine receptor (nAChR) function by a mechanism that may involve α7 and α4β2-nAChR subtypes. Additionally, the beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE), the rate-limiting enzyme in the pathogenic Aβ production pathway, is expressed at high levels in hippocampal and cortical regions of AD brains. We measured hippocampal area CA1 protein levels of BACE and α7- and α4β2-nAChR subunits using an Aβ rat model of AD (14-d osmotic pump i.c.v. infusion of 300 pmol/d Aβ peptides) in the presence and absence of chronic stress and/or chronic nicotine treatment. There was a significant increase in the levels of BACE in Aβ-infused rats, which were markedly intensified by chronic (4-6 wk) stress, but were normalized in Aβ rats chronically treated with nicotine (1 mg/kg b.i.d.). The levels of the three subunits α7, α4 and β2 were significantly decreased in Aβ rats, but these were also normalized in Aβ rats chronically treated with nicotine. Chronic stress did not further aggravate the reduction of nAChRs in Aβ-infused rats. The increased BACE levels and decreased nAChR levels, which are established hallmarks of AD, provide additional support for the validity of the Aβ i.c.v.-infused rat as a model of AD.     

Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer's disease

Amyloid β (Aβ) peptides have long been viewed as a potential target for Alzheimer's disease (AD). Aggregation of Aβ peptides in the brain tissue is believed to be an exclusively pathological process. Therefore, blocking the initial stages of Aβ peptide aggregation with small molecules could hold considerable promise as the starting point for the development of new therapies for AD. Recent rapid progresses in our understanding of toxic amyloid assembly provide a fresh impetus for this interesting approach. Here, we discuss the problems, challenges and new concepts in targeting Aβ peptides.     

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.     

Peptides inhibiting specific cleaving activities of presenilins

Genetic and biological studies provide evidence that the deposition of amyloid-β peptide contributes to the etiology of Alzheimer's disease (AD). Amyloid-β peptides are generated from amyloid-β precursor protein by β- and γ-secretases that are plausible molecular targets for AD treatment. γ-Secretase is an intramembrane-cleaving aspartic protease that is composed of a membrane protein complex containing presenilin. This patent describes a method to inhibit γ-secretase-mediated cleavage by new cell-permeable peptides that are designed on the basis of the interaction mode of amyloid-β precursor protein and presenilin. This patent provides a new strategy for the modulation of the γ-secretase activity towards the development of AD therapeutics.     

PP1 inhibition by Aβ peptide as a potential pathological mechanism in Alzheimer's disease

Abnormal protein phosphorylation has been associated with several neurodegenerative disorders, including Alzheimer's disease (AD). Aβ is the toxic peptide that results from proteolytic cleavage of the Alzheimer's amyloid precursor protein, a process where protein phosphatases are known to impact. The data presented here demonstrates that protein phosphatase 1 (PP1), an abundant neuronal serine/threonine-specific phosphatase highly enriched in dendritic spines, is specifically inhibited by Aβ peptides both in vitro and ex vivo. Indeed, the pathologically relevant Aβ_1–40 and Aβ_1–42 peptides, as well as Aβ_25–35, specifically inhibit PP1 with low micromolar potency, as compared to inactive controls and other disease related peptides (e.g. the prion related Pr_118–135 and Pr_106–126). Interestingly, PP1 inhibition is increased by Aβ aggregation, indicating a possible direct neurotoxic effect of the aggregated peptide. PP1 involvement in processes like long-term depression, memory and learning, and synaptic plasticity, prompt us to suggest that PP1 may constitute an important physiological target for Aβ and, therefore, increased Aβ production and/or aggregation may lead to abnormal PP1 activity and likely contribute to the progressive neuropsychiatric AD condition. Thus, PP1 activity and levels constitute potential biomolecular candidates for diagnostics and therapeutics.     

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.     

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.     

Insight into amyloid structure using chemical probes

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the deposition of amyloids in the brain. One prominent form of amyloid is composed of repeating units of the amyloid-β (Aβ) peptide. Over the past decade, it has become clear that these Aβ amyloids are not homogeneous; rather, they are composed of a series of structures varying in their overall size and shape and the number of Aβ peptides they contain. Recent theories suggest that these different amyloid conformations may play distinct roles in disease, although their relative contributions are still being discovered. Here, we review how chemical probes, such as Congo red, thioflavin T and their derivatives, have been powerful tools for the better understanding of amyloid structure and function. Moreover, we discuss how design and deployment of conformationally selective probes might be used to test emerging models of AD.     

Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer’s disease patients

Introduction: Currently available drugs against Alzheimer’s disease (AD) target cholinergic and glutamatergic neurotransmissions without affecting the underlying disease process. Putative disease-modifying drugs are in development and target β-amyloid (Aβ) peptide and tau protein, the principal neurophatological hallmarks of the disease.

Areas covered: Phase III clinical studies of emerging anti-Aβ drugs for the treatment of AD were searched in US and EU clinical trial registries and in the medical literature until May 2016.

Expert opinion: Drugs in Phase III clinical development for AD include one inhibitor of the β-secretase cleaving enzyme (BACE) (verubecestat), three anti-Aβ monoclonal antibodies (solanezumab, gantenerumab, and aducanumab), an inhibitor of receptor for advanced glycation end products (RAGE) (azeliragon) and the combination of cromolyn sodium and ibuprofen (ALZT-OP1). These drugs are mainly being tested in subjects during early phases of AD or in subjects at preclinical stage of familial AD or even in asymptomatic subjects at high risk of developing AD. The hope is to intervene in the disease process when it is not too late. However, previous clinical failures with anti-Aβ drugs and the lack of fully understanding of the pathophysiological role of Aβ in the development of AD, put the new drugs at substantial risk of failure.     

β-Amyloid therapies in Alzheimer’s disease

Neurones in the brain produce β-amyloid (Aβ) fragments from a larger precursor molecule termed the amyloid precursor protein (APP). When released from the cell, these protein fragments may accumulate in extracellular amyloid plaques and consequently hasten the onset and progression of Alzheimer’s disease (AD). β-Amyloid fragments are generated through the action of specific proteases within the cell. Two of these enzymes, β- and γ-secretase, are particularly important in the formation of Aβ as they cleave within the APP protein to give rise to the N-terminal and C-terminal ends of the Aβ fragment, respectively. Consequently, many researchers are investigating therapeutic approaches that inhibit either β- or γ-secretase activity, with the ultimate goal of limiting Aβ production. An alternative AD therapeutic approach that is being investigated is to employ anti-Aβ antibodies to dissolve plaques that have already formed. Both of these approaches focus on the possibility that accrual of Aβ leads to neuronal degeneration and cognitive impairment characterised by AD and test the hypothesis that limiting Aβ deposition in neuritic plaques may be an effective treatment for AD.     

Aβ的神经毒性及治疗

Aβ（β-amyloid peptides,Aβ）是阿尔茨海默症（Alzheimer＇s disease,AD）发病过程中的核心因子。随着研究的逐渐深入,越来越多的证据表明Aβ在AD的发生、发展中起到主导作用。本综述主要针对Aβ的神经毒性及其复杂的分子机制展开叙述,而后同时就其神经毒性机制展开研究两大类治疗药物。     

以淀粉样蛋白Aβ为靶点治疗阿尔茨海默病的研究进展

阿尔茨海默病(Alzheimer’s Disease,AD)是一种以进行性认知功能减退及行动和社会适应能力下降为基本特征的神经退行性疾病,目前临床上仍缺乏有效的药物和治疗手段。已有大量研究表明淀粉样蛋白聚集型β-淀粉样蛋白(β-amy-loid,Aβ)可能是AD发生的原发性病理因素之一,并提出Aβ是目前AD治疗药物研发中主要的靶点之一。本文综述了以Aβ为靶点治疗AD的最新研究概况,旨在为AD的新药研发提供一些参考。     

The "aged garlic extract:" (AGE) and one of its active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for Alzheimer's disease (AD)

Alzheimer's disease (AD) is the most common form of dementia in the older people and 7(th) leading cause of death in the United States. Deposition of amyloid-beta (Aβ) plaques, hyperphosphorylation of microtubule associated protein tau (MAPT), neuroinflammation and cholinergic neuron loss are the major hallmarks of AD. Deposition of Aβ peptides, which takes place years before the clinical onset of the disease can trigger hyperphophorylation of tau proteins and neuroinflammation, and the latter is thought to be primarily involved in neuronal and synaptic damage seen in AD. To date, four cholinesterase inhibitors or ChEI (tacrine, rivastigmine, donepezil and galantamine) and a partial NMDA receptor antagonist (memantine) are the only approved treatment options for AD. However, these drugs fail to completely cure the disease, which warrants a search for newer class of targets that would eventually lead to effective drugs for the treatment of AD. In addition to selected pharmacological agents, botanical and medicinal plant extracts are also being investigated. Apart from its culinary use, garlic (Allium sativum) is being used to treat several ailments like cancer and diabetes. Herein we have discussed the effects of a specific 'Aged Garlic Extract' (AGE) and one of its active ingredients, S-allyl-L-cysteine (SAC) in restricting several pathological cascades related to the synaptic degeneration and neuroinflammatory pathways associated with AD. Thus, based on the reported positive preliminary results reviewed herein, further research is required to develop the full potential of AGE and/or SAC into an effective preventative strategy for AD.     

Advances in the identification of γ-secretase inhibitors for the treatment of Alzheimer's disease

INTRODUCTION: In an attempt of altering the natural history of Alzheimer's disease (AD), several compounds have been developed with the aim of inhibiting γ-secretase, the enzymatic complex generating β-amyloid (Aβ) peptides (Aβ(1 - 40) and Aβ(1 - 42)), from amyloid precursor protein (APP). APP is believed to be involved in the pathophysiological cascade of AD. AREAS COVERED: This article briefly reviews the profile of γ-secretase inhibitors that have reached the clinic. The paper reviews studies from the primary English literature on γ-secretase inhibitors published before November 2011, searching through the PubMed database of NCBI by author and the following keywords: drugs targeting β-amyloid, γ-secretase inhibitors, dementia syndromes and Alzheimer's disease. EXPERT OPINION: Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these compounds on brain Aβ deposition after prolonged administration. γ-Secretase inhibitors may cause significant toxicity in experimental animals and in humans believed to be associated with the inhibition of the cleavage of Notch, a transmembrane receptor involved in regulating cell-fate decisions. Unfortunately, two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of a detrimental cognitive and functional effects of the drug, possibly due to its lack of selectivity on APP processing. New APP-selective γ-secretase inhibitors are being developed with the hope of overcoming the previous setbacks.     

ABCA1 is Necessary for Bexarotene-Mediated Clearance of Soluble Amyloid Beta from the Hippocampus of APP/PS1 Mice

Alzheimer’s disease (AD) is characterized by impaired clearance of amyloid beta (Aβ) peptides, leading to the accumulation of Aβ in the brain and subsequent neurodegeneration and cognitive impairment. ApoE plays a critical role in the proteolytic degradation of soluble forms of Aβ. This effect is dependent upon lipidation of ApoE by ABCA1-mediated transfer of phospholipids and cholesterol. ApoE and ABCA1 are induced by the action of the RXR agonist, bexarotene. We have previously shown that bexarotene reduces Aβ levels in AD mouse models and we have hypothesized that this effect requires ABCA1-mediated lipidation of ApoE. To test this hypothesis, we crossed ABCA1-deficient (ABCA1 KO) mice with the APP/PS1 model of AD. Aged ABCA1 WT and ABCA1 KO APP/PS1 mice were treated for 7 days with vehicle or bexarotene (100 mg/kg/day). Bexarotene reduced levels of soluble Aβ 1–40 and 1–42 in the hippocampus of ABCA1 WT but not ABCA1 KO APP/PS1 mice. In contrast, insoluble levels of Aβ, and plaque loads were unaffected by bexarotene in this study. ABCA1 KO mice had increased levels of inflammation compared with ABCA1 WT mice. Bexarotene also increased most inflammatory gene markers evaluated. The effect of bexarotene on microglial inflammatory profiles, however, was independent of ABCA1 genotype. Importantly, bexarotene ameliorated deficits in novel object recognition in ABCA1 WT but not ABCA1 KO APP/PS1 mice. These data indicate that ABCA1-induced lipidation of ApoE is necessary for the ability of bexarotene to clear hippocampal soluble Aβ and ameliorate cognitive deficits.     

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.     

Anti-amyloidogenic effects of ID1201, the ethanolic extract of the fruits of Melia toosendan,through activation of the phosphatidylinositol 3-kinase/Akt pathway

Amyloid beta (Aβ) peptides, which are generated from amyloid precursor protein (APP), are thought to play a major role in the pathogenesis of Alzheimer's disease (AD). This study investigated the anti-amyloidogenic effects of the ethanolic extract of Meliae Fructus (ID1201) using human embryonic kidney 293 cells with stably expressed human wild-type or Swedish mutant APP695 and β-secretase 1. ID1201 treatment enhanced the non-amyloidogenic metabolism of APP; increases in soluble APPα levels and decreases in soluble APPβ and Aβ levels resulted from the α-secretase activation through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. In addition, ID1201-treated 5 × familial AD (FAD) mice with 5 mutations in APP and presenilin 1 showed reduced levels of Aβ and amyloid plaques in the brain relative to those of 5 × FAD mice with vehicle treatments. These results indicate that ID1201 possesses anti-amyloidogenic effects via the activation of the PI3K/Akt pathway, suggesting that it is a potential therapeutic agent for AD.     

Icariin decreases neuro-pathogenesis and improves learning and memory functions in Tg2576 mice

Alzheimer′s disease(AD) is one of the most common neurodegenerative diseases,showing progressive memory and cognitive deficits.The predominant neuropathological features of AD are extracellular senile plaques(SP) composed by over expression of amyloid beta protein(Aβ),hyperphosphorylation of Tau protein forming the neurofibrillary tangles(NFTs) and neuronal loss in the specific brain subregions.However,the cause of dementia of AD are still not known,the neurotoxicity of over expressed Aβ coming from the proteolysis of amyloid precursor protein(APP) may play a important role.Aβ neurotoxicity has been widely reported in vitro and in vivo,including the impairment of long term potentiation(LTP),disruption of synaptic plasticity.Aβ also triggered neuron inflammation,and disturbed neurogenesis.caused neuronal oxidative damage and apoptosis,eventually resulted in memory loss At this moment,there are no effective pharmacologic interventions that could halt the progression of AD.Current pharmacotherapies,such as acetylcholinesterase inhibitors including donepezil,rivastigmine and galantamine,and a NMDA antagonist,memantine,improve symptoms but do not block the disease progression.New strategies to slow and/or reverse the pathogenesis of patients with AD are greatly needed.Traditional Chinese Medicine such as icariin may provide an unique opportunity for seeking more safe and effective therapies for AD.In this study we were examine the protective effect of icariin on Tg2576 mice,a well established animal model of AD.Our results demonstrated that chronic treatment of Tg2576 mice with icariin from age of 8 to 11 months,could improve the memory function of Tg2576 mice.In addition,icariin decreased the APP,Aβ levels,and amyloid plaque number in Tg2576 mouse brain.Finally,icariin promoted cell proliferation and differentiation into neuron in the dentate gyrus(DG) of hippocampus in aged Tg2576 mouse.Neurogenesis following icariin administration may due to the decrease of Aβ levels and phosphodiesterase type 5(PDE5),amelioration of the Aβ neurotoxicity,and increase of brain-derived neurotrophic factor(BDNF) expression in mouse brain.In summary,aged Tg2576 mice deministrated neuropathogenesis and cognitive deficits in thebrain,.Chronic treatment of icariin in Tg2576 mice significantly decreased the neuropathogenesis and improved cognitive function.Icariin stimulates neurogenesis in aged Tg2576 mice displayed further neuro-protection in aged brain.Our results provide solid evidence in support that icariin could be a potential compound for AD therapy.     

Pathological changes induced by amyloid-β in Alzheimer's disease

The pathologic hallmarks of Alzheimer's disease (AD) include senile plaque, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration. Senile plaque and NFTs are formed by accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, respectively. Progressive synaptic dysfunction and loss closely correlate with cognitive deficits in AD. Based on studies of the genes responsible for familial AD and temporal patterns of pathologic changes in AD brains, the Aβ accumulation is thought to be a primary event that influences other AD pathologies in the developmental cascade of AD. However, the details of Aβ effects on the other AD pathologies remain poorly understood. In this review, we provide an overview of the effects of Aβ in AD brains, especially focusing on synaptic dysfunction and microglia. We have recently found abnormal accumulation of a key molecule for actin assembly in NFTs of AD brains, and it was revealed that the accumulation requires not only tau pathology but also an Aβ burden in a study using transgenic mouse models of AD. Synaptic integrity is morphologically maintained by the precise regulation of actin assembly. Therefore, the results suggest the possibility that Aβ may promote NFT maturation and induce synaptic dysfunction through the disturbance of actin assembly. Thus Aβ seems to be a promoting factor in brain aging. On the other hand, we have studied microglial phagocytic ability for a compensatory pathologic reaction to Aβ accumulation. Further studies on the Aβ-dependent AD pathologies may contribute to determining novel mechanisms of AD development and new therapeutic targets in 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.