CXCL8 protects human neurons from amyloid-β-induced neurotoxicity: relevance to Alzheimer's disease

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by amyloid-β (Aβ) deposition in senile plaques colocalized with activated microglia and astrocytes. Recent studies suggest that CXCL8 is involved in the AD pathogenesis. The objective of this study was to determine the cellular sources of CXCL8 in the central nervous system during AD pathogenesis, and investigate the effects of CXCL8 on neuronal survival and/or functions. Our results showed significantly higher CXCL8 levels in AD brain tissue lysates as compared to those of age-matched controls. Upon Aβ and/or pro-inflammatory cytokine stimulation, microglia, astrocytes and neurons were all capable of CXCL8 production in vitro. Although CXCL8-alone did not alter neuronal survival, it did inhibit Aβ-induced neuronal apoptosis and increased neuronal brain-derived neurotrophic factor (BDNF) production. We conclude that microglia, astrocytes and neurons, all contribute to the enhanced CXCL8 levels in the CNS upon Aβ and/or pro-inflammatory cytokine stimulation. Further, CXCL8 protects neurons possibly by paracrine or autocrine loop and regulates neuronal functions, therefore, may play a protective role in the AD pathogenesis.     

4-Hydroxynonenal-Derived Advanced Lipid Peroxidation End Products Are Increased in Alzheimer's Disease

Abstract: Recent studies have demonstrated oxidative damage is one of the salient features of Alzheimer's disease (AD). In these studies, glycoxidation adduction to and direct oxidation of amino acid side chains have been demonstrated in the lesions and neurons of AD. To address whether lipid damage may also play an important pathogenic role, we raised rabbit antisera specific for the lysine-derived pyrrole adducts formed by lipid peroxidation-derived 4-hydroxynonenal (HNE). These antibodies were used in immunocytochemical evaluation of brain tissue from AD and age-matched control patients. HNE-pyrrole immunoreactivity not only was identified in about half of all neurofibrillary tangles, but was also evident in neurons lacking neurofibrillary tangles in the AD cases. In contrast, few senile plaques were labeled, and then only the dystrophic neurites were weakly stained, whereas the amyloid-β deposits were unlabeled. Age-matched controls showed only background HNE-pyrrole immunoreactivity in hippocampal or cortical neurons. In addition to providing further evidence that oxidative stress-related protein modification is a pervasive factor in AD, the known neurotoxicity of HNE suggests that lipid peroxidation may also play a role in the neuronal death in AD that underlies cognitive deficits.     

Decreasing oxidative stress and neuroinflammation with a multifunctional peptide rescues memory deficits in mice with Alzheimer disease

Alzheimer disease (AD) is characterized by extracellular senile plaques, intracellular neurofibrillary tangles, and memory loss. Aggregated amyloid-β (Aβ), oxidative stress, and inflammation have pivotal roles in the pathogenesis of AD. Therefore, the inhibition of Aβ-induced neurotoxicity, oxidative stress, and inflammation is a potential therapeutic strategy for the treatment of AD. In this study, a heptapeptide, isolated from a Ph.D.-C7C library by phage display, attenuated Aβ42-induced cytotoxicity in SH-SY5Y neuroblastoma cells and reduced Aβ42-induced oxidative stress by decreasing the production of reactive oxygen species and glutathione disulfide. As a result, glutathione level increased and superoxide dismutase and glutathione peroxidase activities were enhanced in vitro and in vivo. This peptide also suppressed the inflammatory response by decreasing the release of proinflammatory cytokines, such as tumor necrosis factor α and interleukin 1β, in microglia and by reducing microgliosis and astrogliosis in AD transgenic mice. This peptide was intracerebroventricularly administered to APPswe/PS1dE9 transgenic mice. We found that this peptide significantly improved spatial memory and reduced the amyloid plaque burden and soluble and insoluble Aβ levels. Our findings suggest that this multifunctional peptide has therapeutic potential for an Aβ-targeted treatment of AD.     

老年痴呆症中神经递质释放异常的机理

阿尔茨海默症(Alzheimer’s disease,AD)是以胞外淀粉样蛋白(amyloid-β,Aβ)沉积和胞内神经纤维缠结为病理特征的神经退行性疾病。AD典型症状的出现与中枢神经系统突触数量的减少密切相关,因此,明确AD早期突触数量还没有明显降低时突触功能失调的机制对AD的临床诊治具有十分重要的意义。寡聚Aβ、早老素功能缺失等因素造成的突触前神经递质释放异常很有可能是AD突触功能异常的上游机制。对AD中神经递质释放异常的现象和机制进行综述,并对这一领域存在的开放问题作一归纳。     

Early calcium dysregulation in Alzheimer’s disease: setting the stage for synaptic dysfunction

Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder with no known cure or clear understanding of the mechanisms involved in the disease process. Amyloid plaques, neurofibrillary tangles and neuronal loss, though characteristic of AD, are late stage markers whose impact on the most devastating aspect of AD, namely memory loss and cognitive deficits, are still unclear. Recent studies demonstrate that structural and functional breakdown of synapses may be the underlying factor in AD-linked cognitive decline. One common element that presents with several features of AD is disrupted neuronal calcium signaling. Increased intracellular calcium levels are functionally linked to presenilin mutations, ApoE4 expression, amyloid plaques, tau tangles and synaptic dysfunction. In this review, we discuss the role of AD-linked calcium signaling alterations in neurons and how this may be linked to synaptic dysfunctions at both early and late stages of the disease.     

PKR knockout in the 5xFAD model of Alzheimer's disease reveals beneficial effects on spatial memory and brain lesions

Brain lesions in Alzheimer's disease (AD) include amyloid plaques made of Aβ peptides and neurofibrillary tangles composed of hyperphosphorylated tau protein with synaptic and neuronal loss and neuroinflammation. Aβ oligomers can trigger tau phosphorylation and neuronal alterations through activation of neuronal kinases leading to progressive cognitive decline. PKR is a ubiquitous pro‐apoptotic serine/threonine kinase, and levels of activated PKR are increased in AD brains and AD CSF. In addition, PKR regulates negatively memory formation in mice. To assess the role of PKR in an AD in vivo model, we crossed 5xFAD transgenic mice with PKR knockout (PKRKO) mice and we explored the contribution of PKR on cognition and brain lesions in the 5xFAD mouse model of AD as well as in neuron–microglia co‐cultures exposed to the innate immunity activator lipopolysaccharide (LPS). Nine‐month‐old double‐mutant mice revealed significantly improved memory consolidation with the new object location test, starmaze test, and elevated plus maze test as compared to 5xFAD mice. Brain amyloid accumulation and BACE1 levels were statistically decreased in double‐mutant mice. Apoptosis, neurodegeneration markers, and synaptic alterations were significantly reduced in double‐mutant mice as well as neuroinflammation markers such as microglial load and brain cytokine levels. Using cocultures, we found that PKR in neurons was essential for LPS microglia‐induced neuronal death. Our results demonstrate the clear involvement of PKR in abnormal spatial memory and brain lesions in the 5xFAD model and underline its interest as a target for neuroprotection in AD.     

阿尔茨海默病与炎性调控

阿尔茨海默病 （AD） 是毁灭性的神经退行性损伤疾病,其特点是细胞外聚积β淀粉样蛋白（Aβ）形成淀粉样斑块和细胞内异常高度磷酸化 tau 蛋白导致神经纤维缠结(neurobrillary tangles）.基于上述特点提出的β淀粉样蛋白假说和tau的高度磷酸化假说,仍不能完全解释其发病机理和神经元的退行性损伤.目前,炎症小体在阿尔茨海默病的病理过程中引起的炎症和组织损伤引起高度关注.因此研究AD患者中炎症小体如何激活、组装、并诱发细胞炎性介质的高表达,可能对深入研究AD病理机制和治疗靶点的突破提供一种新的解释,本文主要针对这一研究领域的进展加以简要的概述介绍.     

Convergence of Amyloid-β and Tau Pathologies on Mitochondria In Vivo

The histopathological characteristics of Alzheimer’s disease (AD) are amyloid-β (Aβ) containing plaques and neurofibrillary tangles (NFTs) as well as neuronal and synaptic loss. Until today, the underlying mechanisms of the interplay of plaques and tangles remained unresolved. There is increasing evidence that mitochondrial dysfunction might be a possible link, as revealed by studies in several APP and tau transgenic mouse models. Recently, we examined mitochondrial function in a novel triple transgenic mouse model (pR5/APP/PS2)—^tripleAD mice—that combines both pathologic features of the disease in brain. Using comparative, quantitative proteomics (iTRAQ) and mass spectroscopy, we found a massive deregulation of 24 proteins, of which one third were mitochondrial proteins mainly related to complexes I and IV of the oxidative phosphorylation system (OXPHOS). Remarkably, deregulation of complex I was related to tau, whereas deregulation of complex IV was Aβ dependent, both at the protein and activity levels. The ^tripleAD mice showed synergistic effects of Aβ and tau already at the age of 8 months, resulting in a depolarized mitochondrial membrane potential. At 12 months, the strongest defects on OXPHOS, synthesis of ATP and reactive oxygen species, were exhibited in the ^tripleAD mice, again emphasizing synergistic, age-associated effects of Aβ and tau in impairing mitochondria. This review highlights the convergence of Aβ and tau on mitochondria and establishes a molecular link in AD pathology in vivo.     

阿尔茨海默病中的β-淀粉样蛋白和Tau蛋白

阿尔茨海默病(Alzheimer’s disease,AD)是与年龄相关的神经退行性疾病。记忆障碍通常是AD最早期和最明显的特征。β-淀粉样蛋白(amyloid-β,Aβ)沉淀(老年斑)、Tau蛋白引起的神经纤维缠结是AD的典型病理特征。许多研究证实两者之间存在着极为复杂的互为因果关系,共同造成神经元的损害。     

Is increased redox-active iron in Alzheimer disease a failure of the copper-binding protein ceruloplasmin?

One of the most striking features of Alzheimer disease (AD) is an accumulation of iron in neurofibrillary tangles and senile plaques. Intriguingly, this iron is found as both iron (II) and iron (III) and is redox-active. To address the issue of whether such iron participates in redox cycling, it was essential to investigate how iron (II) accumulates, since oxidation of iron (II) can lead to the generation of reactive oxygen species. To begin to address this issue, here we investigated ceruloplasmin, a key protein involved in the regulation of the redox state of iron by converting iron (II) to iron (III). Cases of AD and age-matched controls, obtained at autopsy with similar postmortem intervals, display similar levels of ceruloplasmin immunoreactivity that is mainly confined to neurons. However, in marked contrast, cases of AD show a significant increase in ceruloplasmin within the neuropil determined by immunoblot analysis of tissue homogenates as well as a generalized increased neuropil staining. Together, these findings suggest that neuronal induction of ceruloplasmin is feeble in AD, even while there is an increase in tissue ceruloplasmin. Therefore, a failure of neuronal ceruloplasmin to respond to iron may be an important factor that then leads to an accumulation of redox-active iron in neurons in AD.     

Tau Proteins and Tauopathies in Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive function deficits. There are two major pathological hallmarks that contribute to the pathogenesis of AD which are the presence of extracellular amyloid plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Despite extensive research that has been done on Aβ in the last two decades, therapies targeting Aβ were not very fruitful at treating AD as the efficacy of Aβ therapies observed in animal models is not reflected in human clinical trials. Hence, tau-directed therapies have received tremendous attention as the potential treatments for AD. Tauopathies are closely correlated with dementia and immunotherapy has been effective at reducing tau pathology and improving cognitive deficits in animal models. Thus, in this review article, we discussed the pathological mechanism of tau proteins, the key factors contributing to tauopathies, and therapeutic approaches for tauopathies in AD based on the recent progress in tau-based research.     

Secretases as therapeutic targets for Alzheimer's disease

Accumulation of amyloid-β (Aβ) is widely accepted as the key instigator of Alzheimer’s disease (AD). The proposed mechanism is that accumulation of Aβ results in inflammatory responses, oxidative damages, neurofibrillary tangles and, subsequently, neuronal/synaptic dysfunction and neuronal loss. Given the critical role of Aβ in the disease process, the proteases that produce this peptide are obvious targets. The goal would be to develop drugs that can inhibit the activity of these targets. Protease inhibitors have proved very effective for treating other disorders such as AIDS and hypertension. Mutations in APP (amyloid-β precursor protein), which flanks the Aβ sequence, cause early-onset familial AD, and evidence has pointed to the APP-to-Aβ conversion as a possible therapeutic target. Therapies aimed at modifying Aβ-related processes aim higher up the cascade and are therefore more likely to be able to alter the progression of the disease. However, it is not yet fully known whether the increases in Aβ levels are merely a result of earlier events that were already causing the disease.     

Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity

Neuroinflammation and associated neuronal dysfunction mediated by activated microglia play an important role in the pathogenesis of Alzheimer disease (AD). Microglia are activated by aggregated forms of amyloid-β protein (Aβ), usually demonstrated in vitro by stimulating microglia with micromolar concentrations of fibrillar Aβ, a major component of amyloid plaques in AD brains. Here we report that amyloid-β oligomer (AβO), at 5-50 nm, induces a unique pattern of microglia activation that requires the activity of the scavenger receptor A and the Ca(2+)-activated potassium channel KCa3.1. AβO treatment induced an activated morphological and biochemical profile of microglia, including activation of p38 MAPK and nuclear factor κB. Interestingly, although increasing nitric oxide (NO) production, AβO did not increase several proinflammatory mediators commonly induced by lipopolyliposaccharides or fibrillar Aβ, suggesting that AβO stimulates both common and divergent pathways of microglia activation. AβO at low nanomolar concentrations, although not neurotoxic, induced indirect, microglia-mediated damage to neurons in dissociated cultures and in organotypic hippocampal slices. The indirect neurotoxicity was prevented by (i) doxycycline, an inhibitor of microglia activation; (ii) TRAM-34, a selective KCa3.1 blocker; and (iii) two inhibitors of inducible NO synthase, indicating that KCa3.1 activity and excessive NO release are required for AβO-induced microglial neurotoxicity. Our results suggest that AβO, generally considered a neurotoxin, may more potently cause neuronal damage indirectly by activating microglia in AD.     

New insights into the role of TREM2 in Alzheimer’s disease

Alzheimer’s disease (AD) is the leading cause of dementia. The two histopathological markers of AD are amyloid plaques composed of the amyloid-β (Aβ) peptide, and neurofibrillary tangles of aggregated, abnormally hyperphosphorylated tau protein. The majority of AD cases are late-onset, after the age of 65, where a clear cause is still unknown. However, there are likely different multifactorial contributors including age, enviornment, biology and genetics which can increase risk for the disease. Genetic predisposition is considerable, with heritability estimates of 60–80%. Genetic factors such as rare variants of TREM2 (triggering receptor expressed on myeloid cells-2) strongly increase the risk of developing AD, confirming the role of microglia in AD pathogenesis. In the last 5 years, several studies have dissected the mechanisms by which TREM2, as well as its rare variants affect amyloid and tau pathologies and their consequences in both animal models and in human studies. In this review, we summarize increases in our understanding of the involvement of TREM2 and microglia in AD development that may open new therapeutic strategies targeting the immune system to influence AD pathogenesis.     

Calcium signaling in Alzheimer's disease & therapies

Alzheimer's disease (AD) is the most common type of dementia and is characterized by the accumulation of amyloid (Aβ) plaques and neurofibrillary tangles in the brain. Much attention has been given to develop AD treatments based on the amyloid cascade hypothesis; however, none of these drugs had good efficacy at improving cognitive functions in AD patients suggesting that Aβ might not be the disease origin. Thus, there are urgent needs for the development of new therapies that target on the proximal cause of AD. Cellular calcium (Ca²⁺) signals regulate important facets of neuronal physiology. An increasing body of evidence suggests that age-related dysregulation of neuronal Ca²⁺ homeostasis may play a proximal role in the pathogenesis of AD as disrupted Ca²⁺ could induce synaptic deficits and promote the accumulation of Aβ plaques and neurofibrillary tangles. Given that Ca²⁺ disruption is ubiquitously involved in all AD pathologies, it is likely that using chemical agents or small molecules specific to Ca²⁺ channels or handling proteins on the plasma membrane and membranes of intracellular organelles to correct neuronal Ca²⁺ dysregulation could open up a new approach to AD prevention and treatment. This review summarizes current knowledge on the molecular mechanisms linking Ca²⁺ dysregulation with AD pathologies and discusses the possibility of correcting neuronal Ca²⁺ disruption as a therapeutic approach for AD.     

LPS-mediated cell surface expression of CD74 promotes the proliferation of B cells in response to MIF

Macrophage migration inhibitory factor (MIF) is a chemokine-like inflammatory cytokine, which plays a pivotal role in the pathogenesis of inflammatory and cardiovascular diseases as well as cancer. We previously identified MIF as a novel B cell chemokine that promotes B cell migration through non-cognate interaction with the CXC chemokine receptor CXCR4 and CD74, the surface form of MHC class II invariant chain. In this study, we have analyzed the regulation of the MIF receptors under inflammatory conditions by investigating the impact of lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) on CD74 and CXCR4 expression in B lymphocytes. We found that both LPS and TNF-α stimulation of primary B cells and the human B myeloma cell line RPMI-8226 enhanced protein expression as well as mRNA levels of CD74 in a time- and dose-dependent manner. By contrast, no effect on CXCR4 expression was observed. Selective inhibition of IκBα phosphorylation significantly attenuated LPS-induced expression of CD74, suggesting the contribution of NF-κB signaling pathways to the regulation of CD74 expression. Importantly, individual or simultaneous blockade of MIF or CD74 using specific neutralizing antibodies markedly affected B cell proliferation after LPS exposure. Taken together, our findings unveil a connection between the pro-proliferative activity of MIF/CD74 signaling in B cells and inflammation, offering novel target mechanisms in inflammatory cardiovascular or autoimmune pathogenesis.     

脑锌代谢与阿尔茨海默病

锌是中枢神经系统含量最丰富的过渡金属元素之一,对维持中枢神经系统正常生理功能具有重要作用,其稳态失衡与多种疾病有关。阿尔茨海默病是一种多病因神经退行性疾病,以β-淀粉样斑块形成和神经原纤维缠结为主要病理特征。研究表明,脑锌代谢紊乱在阿尔茨海默病发病过程中扮演重要角色,但确切机制尚不十分清楚。综述了脑锌代谢和稳态调控以及锌和锌转运蛋白参与β-淀粉样蛋白沉积与老年斑形成的病理过程,并探讨了金属一蛋白阻尼复合物如何通过恢复脑锌稳态延缓疾病进程、改善患者认知能力的治疗策略。     

Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease

Alzheimer disease (AD) is a neurodegenerative disease which is characterized by the presence of extracellular senile plaques mainly composed of amyloid-beta peptide (Abeta), intracellular neurofibrillary tangles, and selective synaptic and neuronal loss. AD brains revealed elevated levels of oxidative stress markers which have been implicated in Abeta-induced toxicity. In the present work we addressed the hypothesis that oxidative stress occurs early in the development of AD and evaluated the extension of the oxidative stress and the levels of antioxidants in an in vivo model of AD, the triple-transgenic mouse, which develops plaques, tangles, and cognitive impairments and thus mimics AD progression in humans. We have shown that in this model, levels of antioxidants, namely, reduced glutathione and vitamin E, are decreased and the extent of lipid peroxidation is increased. We have also observed increased activity of the antioxidant enzymes glutathione peroxidase and superoxide dismutase. These alterations are evident during the Abeta oligomerization period, before the appearance of Abeta plaques and neurofibrillary tangles, supporting the view that oxidative stress occurs early in the development of the disease.     

An aluminum-based rat model for Alzheimer's disease exhibits oxidative damage, inhibition of PP2A activity, hyperphosphorylated tau, and granulovacuolar degeneration

In Alzheimer's disease (AD), oxidative damage leads to the formation of amyloid plaques while low PP2A activity results in hyperphosphorylated tau that polymerizes to form neurofibrillary tangles. We probed these early events, using brain tissue from a rat model for AD that develops memory deterioration and AD-like behaviors in old age after chronically ingesting 1.6 mg aluminum/kg bodyweight/day, equivalent to the high end of the human dietary aluminum range. A control group consumed 0.4 mg aluminum/kg/day. We stained brain sections from the cognitively-damaged rats for evidence of amyloid plaques, neurofibrillary tangles, aluminum, oxidative damage, and hyperphosphorylated tau. PP2A activity levels measured 238.71+/-17.56 pmol P(i)/microg protein and 580.67+/-111.70 pmol P(i)/microg protein (p<0.05) in neocortical/limbic homogenates prepared from cognitively-damaged and control rat brains, respectively. Thus, PP2A activity in cognitively-damaged brains was 41% of control value. Staining results showed: (1) aluminum-loading occurs in some aged rat neurons as in some aged human neurons; (2) aluminum-loading in rat neurons is accompanied by oxidative damage, hyperphosphorylated tau, neuropil threads, and granulovacuolar degeneration; and (3) amyloid plaques and neurofibrillary tangles were absent from all rat brain sections examined. Known species difference can reasonably explain why plaques and tangles are unable to form in brains of genetically-normal rats despite developing the same pathological changes that lead to their formation in human brain. As neuronal aluminum can account for early stages of plaque and tangle formation in an animal model for AD, neuronal aluminum could also initiate plaque and tangle formation in humans with AD.     

The Neuroprotective Effect of GM-1 Ganglioside on the Amyloid-Beta-Induced Oxidative Stress in PC-12 Cells Mediated by Nrf-2/ARE Signaling Pathway

Neurochemical Research - Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques, tau tangles, neuroinflammation, oxidative stress, and progressive...