Complement activation by islet amyloid polypeptide (IAPP) and alpha-synuclein 112

Complement can damage host tissue when overactivated. Evidence of complement self damage exists for Alzheimer disease (AD), age-related macular degeneration, type 1 diabetes mellitus (T1DM), and Parkinson disease (PD). Known complement activators include Abeta, found in AD, and IgG found in T1DM. We compared their complement activating ability in vitro with those of islet amyloid polypeptide (IAPP), which aggregates in the pancreas of T2DM, and alpha-synuclein (alpha-Syn), which aggregates in PD. We found that IAPP and the alternatively spliced alpha-Syn 112 form, but not full-length alpha-Syn 140, activated complement in vitro. Complement activation may contribute to death of insulin-secreting cells in T2DM or to neuronal death in Parkinson disease (PD) and related synucleinopathies where alpha-Syn 112 occurs. This suggests the possibility of anti-inflammatory treatment in these pathologies. It also suggests that blockers of complement activation may be an appropriate therapeutic target for a range of age-related degenerative diseases.     

综述:金属离子代谢平衡失调与阿尔茨海默病早期发病机制

研究表明,脑内金属离子代谢失衡与阿尔茨海默病(AD)有关,但其机理尚需深入探讨．结合本实验室研究结果,作者对金属离子代谢紊乱与氧化应激,金属离子代谢紊乱与β-淀粉样蛋白、转铁蛋白和转铁蛋白受体、铁调节蛋白、二价金属离子转运体以及天然抗氧化剂通过调节金属离子代谢平衡缓解β-淀粉样蛋白的毒性和保护细胞的作用进行探讨．提出：铁、铜等金属离子缺乏可能主要与AD早期关系密切,而铁、铜等金属离子过载可能主要与AD后期损伤关系密切的学术观点．     

Oxidative stress in Alzheimer disease

Alzheimer disease (AD) is a progressive dementia affecting a large proportion of the aging population. The histopathological changes in AD include neuronal cell death, formation of amyloid plaques and neurofibrillary tangles. There is also evidence that brain tissue in patients with AD is exposed to oxidative stress (e.g., protein oxidation, lipid oxidation, DNA oxidation and glycoxidation) during the course of the disease. Advanced glycation endproducts (AGEs) are present in amyloid plaques in AD, and its extracellular accumulation may be caused by an accelerated oxidation of glycated proteins. AGEs participate in neuronal death causing direct (chemical) and indirect (cellular) free radical production and consequently increase oxidative stress. The development of drugs for the treatment of AD that breaks the vicious cycles of oxidative stress and neurodegeneration offer new opportunities. These approaches include AGE-inhibitors, antioxidants and anti-inflammatory substances, which prevent free radical production.     

Oxidative stress in Alzheimer disease

Alzheimer disease (AD) is a progressive dementia affecting a large proportion of the aging population. The histopathological changes in AD include neuronal cell death, formation of amyloid plaques and neurofibrillary tangles. There is also evidence that brain tissue in patients with AD is exposed to oxidative stress (e.g., protein oxidation, lipid oxidation, DNA oxidation and glycoxidation) during the course of the disease. Advanced glycation endproducts (AGEs) are present in amyloid plaques in AD, and its extracellular accumulation may be caused by an accelerated oxidation of glycated proteins. AGEs participate in neuronal death causing direct (chemical) and indirect (cellular) free radical production and consequently increase oxidative stress. The development of drugs for the treatment of AD that breaks the vicious cycles of oxidative stress and neurodegeneration offer new opportunities. These approaches include AGE-inhibitors, antioxidants and anti-inflammatory substances, which prevent free radical production.Key words: ageing, advanced glycation endproducts, Alzheimer disease, amyloid, oxidative stress     

Activators and inhibitors of the plasminogen system in Alzheimer's disease

Accumulation and deposition of Aβ is one of the main neuropathological hallmarks of Alzheimer's disease (AD) and impaired Aβ degradation may be one mechanism of accumulation. Plasmin is the key protease of the plasminogen system and can cleave Aβ. Plasmin is activated from plasminogen by tissue plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). The activators are regulated by inhibitors which include plasminogen activator inhibitor-1 (PAI-1) and neuroserpin. Plasmin is also regulated by inhibitors including α2-antiplasmin and α2-macroglobulin. Here, we investigate the mRNA levels of the activators and inhibitors of the plasminogen system and the protein levels of tPA, neuroserpin and α2-antiplasmin in post-mortem AD and control brain tissue. Distribution of the activators and inhibitors in human brain sections was assessed by immunoperoxidase staining. mRNA measurements were made in 20 AD and 20 control brains by real-time PCR. In an expanded cohort of 38 AD and 38 control brains tPA, neuroserpin and α2-antiplasmin protein levels were measured by ELISA. The activators and inhibitors were present mainly in neurons and α2-antiplasmin was also associated with Aβ plaques in AD brain tissue. tPA, uPA, PAI-1 and α2-antiplasmin mRNA were all significantly increased in AD compared to controls, as were tPA and α2-antiplasmin protein, whereas neuroserpin mRNA and protein were significantly reduced. α2-macroglobulin mRNA was not significantly altered in AD. The increases in tPA, uPA, PAI-1 and α2-antiplasmin may counteract each other so that plasmin activity is not significantly altered in AD, but increased tPA may also affect synaptic plasticity, excitotoxic neuronal death and apoptosis.     

Nanoparticle and other metal chelation therapeutics in Alzheimer disease

Current therapies for Alzheimer disease (AD) such as the anticholinesterase inhibitors and the latest NMDA receptor inhibitor, Namenda, provide moderate symptomatic delay at various stages of disease, but do not arrest disease progression or supply meaningful remission. As such, new approaches to disease management are urgently needed. Although the etiology of AD is largely unknown, oxidative damage mediated by metals is likely a significant contributor since metals such as iron, aluminum, zinc, and copper are dysregulated and/or increased in AD brain tissue and create a pro-oxidative environment. This role of metal ion-induced free radical formation in AD makes chelation therapy an attractive means of dampening the oxidative stress burden in neurons. The chelator desferioxamine, FDA approved for iron overload, has shown some benefit in AD, but like many chelators, it has a host of adverse effects and substantial obstacles for tissue-specific targeting. Other chelators are under development and have shown various strengths and weaknesses. In this review, we propose a novel system of chelation therapy through the use of nanoparticles. Nanoparticles conjugated to chelators show a unique ability to cross the blood-brain barrier (BBB), chelate metals, and exit through the BBB with their corresponding complexed metal ions. This method may prove to be a safe and effective means of reducing the metal load in neural tissue thus staving off the harmful effects of oxidative damage and its sequelae.     

Metal exposure and Alzheimer's pathogenesis

With the growing aging population in Western countries, Alzheimer's disease (AD) has become a major public health concern. No preventive measure and effective treatment for this burdensome disease is currently available. Genetic, biochemical, and neuropathological data strongly suggest that Abeta amyloidosis, which originates from the amyloidogenic processing of a metalloprotein-amyloid precursor protein (APP), is the key event in AD pathology. However, neurochemical factors that impact upon the age-dependent cerebral Abeta amyloidogenesis are not well recognized. Growing data indicate that cerebral dysregulation of biometals, environmental metal exposure, and oxidative stress contribute to AD pathology. Herein we provided further evidence that both metals (such as Cu) and H(2)O(2) promote formation of neurotoxic Abeta oligomers. Moreover, we first demonstrated that laser capture microdissection coupled with X-ray fluorescence microscopy can be applied to determine elemental profiles (S, Fe, Cu, and Zn) in Abeta amyloid plaques. Clearly the fundamental biochemical mechanisms linking brain biometal metabolism, environmental metal exposure, and AD pathophysiology warrant further investigation. Nevertheless, the study of APP and Abeta metallobiology may identify potential targets for therapeutic intervention and/or provide diagnostic methods for AD.     

Metallobiology and therapeutic chelation of biometals (copper,zinc and iron) in Alzheimer’s disease: Limitations,and current and future perspectives

BackgroundAlzheimer's disease (AD) is the most prevalent cause of cognitive impairment and dementia worldwide. The pathobiology of the disease has been studied in the form of several hypotheses, ranging from oxidative stress, amyloid-beta (Aβ) aggregation, accumulation of tau forming neurofibrillary tangles (NFT) through metal dysregulation and homeostasis, dysfunction of the cholinergic system, and to inflammatory and autophagic mechanism. However, none of these hypotheses has led to confirmed diagnostics or approved cure for the disease.ObjectiveThis review is aimed as a basic and an encyclopedic short course into metals in AD and discusses the advances in chelation strategies and developments adopted in the treatment of the disease. Since there is accumulating evidence of the role of both biometal dyshomeostasis (iron (Fe), copper (Cu), and zinc (Zn)) and metal-amyloid interactions that lead to the pathogenesis of AD, this review focuses on unraveling therapeutic chelation strategies that have been considered in the treatment of the disease, aiming to sequester free and protein-bound metal ions and reducing cerebral metal burden. Promising compounds possessing chemically modified moieties evolving as multi-target ligands used as anti-AD drug candidates are also covered.Results and ConclusionSeveral multidirectional and multifaceted studies on metal chelation therapeutics show the need for improved synthesis, screening, and analysis of compounds to be able to effectively present chelating anti-AD drugs. Most drug candidates studied have limitations in their physicochemical properties; some enhance redistribution of metal ions, while others indirectly activate signaling pathways in AD. The metal chelation process in vivo still needs to be established and the design of potential anti-AD compounds that bi-functionally sequester metal ions as well as inhibit the Aβ aggregation by competing with the metal ions and reducing metal-induced oxidative damage and neurotoxicity may signal a bright end in chelation-based therapeutics of AD.     

Links Between the Pathology of Alzheimer's Disease and Vascular Dementia

The major neuropathological lesions defining Alzheimer's disease (AD) include neurofibrillary tangles and amyloid plaques, which are mainly composed of abnormally phosphorylated tau and amyloid-beta (A beta), respectively. Numerous neuropathological and neuroimaging studies indicate that at least one-third of AD cases are complicated by some degree of vascular pathology, whereas in a similar proportion of patients clinically diagnosed with vascular dementia, AD pathology is also present. Many classical vascular risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia have recently been shown also to increase the risk of AD. Growing evidence suggests that vascular pathology lowers the threshold for the clinical presentation of dementia at a given level of AD-related pathology and potentially directly promotes AD lesions such as A beta plaques. Cerebral ischemia, chronically up-regulates expression of the amyloid precursor protein (APP), which is the precursor to the amyloid beta peptide and damages the blood-brain barrier (BBB), affecting A beta peptide clearance from the brain. Recognition of the importance of these vascular risk factors for AD-related dementia and their treatment will be beneficial not only for preventing cardiac, cerebral, and peripheral complications of vascular disease, but also will likely have a direct impact on the occurrence of sporadic AD in older subjects. In this paper, we review some of the links between vascular risk factors and AD pathology and present data on the direct effect of ischemia on cognitive function and A beta deposition in a mouse model of AD.     

Genetic Knockdown of Brain-Derived Neurotrophic Factor in 3xTg-AD Mice Does Not Alter Aβ or Tau Pathology

Brain-derived neurotrophic factor (BDNF) is a neurotrophin critically involved in cell survival, synaptic plasticity, and memory. BDNF has recently garnered significant attention as a potential therapeutic target for neurodegenerative diseases such as Alzheimer disease (AD), but emerging evidence suggests that BDNF may also be mechanistically involved in the pathogenesis of AD. AD patients have substantially reduced BDNF levels, which may be a result of Aβ and tau pathology. Recent evidence, however, indicates reduced BDNF levels may also serve to drive pathology in neuronal cultures, although this has not yet been established in vivo. To further investigate the mechanistic role of BDNF in AD, we generated 3xTg-AD mice with a heterozygous BDNF knockout (BDNF(+/-)) and analyzed Aβ and tau pathology. Aged 3xTg-AD/BDNF(+/-) mice have significantly reduced levels of brain BDNF, but have comparable levels of Aβ and tau pathology to 3xTg-AD/BDNF(+/+) mice. These findings indicate that chronic reduction of BDNF does not exacerbate the development of Aβ and tau pathology, and instead suggests the reduced BDNF levels found in AD patients are a consequence of these pathologies.     

Molecular isoform distribution and glycosylation of acetylcholinesterase are altered in brain and cerebrospinal fluid of patients with Alzheimer's disease

The glycosylation of acetylcholinesterase (AChE) in CSF was analyzed by lectin binding. AChE from Alzheimer's disease (AD) patients was found to bind differently to two lectins, concanavalin A and wheat germ agglutinin, than AChE from controls. As multiple isoforms of AChE are present in both CSF and brain, we examined whether the abnormal glycosylation of AD AChE was due to changes in a specific molecular isoform. Globular amphiphilic dimeric (G2a) and monomeric (G1a) isoforms of AChE were found to be differentially glycosylated in AD CSF. Glycosylation of AChE was also altered in AD frontal cortex but not in cerebellum and was also associated with an increase in the proportion of light (G2 and G1) isoforms. This study demonstrates that the glycosylation of AChE is altered in the AD brain and that changes in AChE glycosylation in AD CSF may reflect changes in the distribution of brain isoforms. The study also suggests that glycosylation of AChE may be a useful diagnostic marker for AD.     

Hypothesis: apo‐lactoferrin–Galantamine Proteo‐alkaloid Conjugate for Alzheimer's disease Intervention

Alzheimer's disease (AD) is known to be caused by the accumulation of deformed beta amyloid and hyperphosphorylated tau proteins resulting into formation and aggregation of senile plaques and neurofibrillary tangles in the brain. Additionally, AD is associated with the accumulation of iron or metal ions in the brain which causes oxidative stress. Galantamine (Gal) is one of the therapeutic agents that has been approved for the treatment of AD, but still saddled with numerous side effects and could not address the issue of iron accumulation in the brain. The use of metal chelators to address the iron accumulation has not been successful due to toxicity and inability to address the aggregation of the plaques. We therefore hypothesize a combinatorial antioxidant–metal–chelator approach by formulating a single dosage form that has the ability to prevent the formation of free radicals, plaques and accumulation of iron in the brain. This can be achieved by conjugating Gal with apo‐lactoferrin (ApoLf), a natural compound that has high binding affinity for iron, to form an apo‐lactoferrin–galantamine proteo‐alkaloid conjugate (ApoLf–Gal) as a single dosage form for AD management. The conjugation is achieved through self‐assembly of ApoLf which results in encapsulation of Gal. ApoLf changes its conformational structure in the presence of iron; therefore, ApoLf–Gal is proposed to deliver Gal and pick up excess iron when in contact with iron. This strategy has the potential to proffer a dual neuroprotection and neurotherapeutic interventions for the management of AD.     

运动改善阿尔茨海默病的酮体相关机制研究进展

阿尔茨海默病(Alzheimer's disease,AD)是一种多发于老年人群的神经退行性疾病,目前尚无有效治疗AD的药物,而酮体和运动能够为大脑提供保护作用,有效延缓AD的病理进程.β-羟基丁酸(β-hydroxybutyrate,BHB)作为哺乳动物体内含量最高的酮体,不仅可以作为一种替代能源物质,也能作为信号分...     

Neuroinflammation,Gut Microbiome,and Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that develops insidiously and causes dementia finally. There are also clinical complications in advanced dementia, such as eating problems, infections, which will lead to the decline of patients’ life quality, and the rising cost of care for AD to our society. AD will be important public health challenge. Early detection of AD may be a key issue to prevent, delay, and stop the disease. Gut microbiome and neuroinflammation are closely related with nervous system diseases, although the specific mechanism is not clear. This review introduces the relationship between neuroinflammation, gut microbiome, and AD.     

Prostacyclin synthesis by endothelial cells from human umbilical veins: effect of cumulative population doublings

There is a wide range of reported values for prostacyclin (PGI2) synthesis by cultured endothelial cells from human umbilical veins (HUVE). Part of this variation may be due to differences in isolation and culture conditions, but part may be due to previously unstudied variation in the number of population doublings (PDs) which the cells have undergone in vitro. Attention is now shifting to arachidonic acid (AA) metabolism by cells from adult human vessels and these cells may require increased PDs to obtain confluent cultures for testing. Therefore, we have examined the effect of number of cell population doublings as well as number of subcultivations on PGI2 synthesis using HUVE as a model system. Primary and first subcultivation cultures inoculated at high density, so that PDs at confluence were less than 4, synthesized 10 times as much PGI2 as the same isolates inoculated at low density with PDs greater than 4. Isolates inoculated and subcultivated so that the PDs at confluence after the fourth subcultivation were less than 6, showed 50% less PGI2 synthesis between the primary and first subcultivation and between the first and second subcultivations. Isolates with less than 4 PDs after the fourth subcultivation were carried further to determine the effect of extensive subcultivation. Four of six isolates showed a sudden increase in PGI2 synthesis which occurred between subcultivations 5 and 12 (PDs 4-6). These results demonstrate that AA metabolism is markedly affected by growth in culture and serial subcultivation.     

Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease

Characterized as a peripheral metabolic disorder and a degenerative disease of the central nervous system respectively, it is now widely recognized that type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share several common abnormalities including impaired glucose metabolism, increased oxidative stress, insulin resistance and amyloidogenesis. Several recent studies suggest that this is not an epiphenomenon, but rather these two diseases disrupt common molecular pathways and each disease compounds the progression of the other. For instance, in AD the accumulation of the amyloid-beta peptide (Aβ), which characterizes the disease and is thought to participate in the neurodegenerative process, may also induce neuronal insulin resistance. Conversely, disrupting normal glucose metabolism in transgenic animal models of AD that over-express the human amyloid precursor protein (hAPP) promotes amyloid-peptide aggregation and accelerates the disease progression. Studying these processes at a cellular level suggests that insulin resistance and Aβ aggregation may not only be the consequence of excitotoxicity, aberrant Ca²⁺ signals, and proinflammatory cytokines such as TNF-α, but may also promote these pathological effectors. At the molecular level, insulin resistance and Aβ disrupt common signal transduction cascades including the insulin receptor family/PI3 kinase/Akt/GSK3 pathway. Thus both disease processes contribute to overlapping pathology, thereby compounding disease symptoms and progression.     

Annexin 5 and apolipoprotein E2 protect against Alzheimer's amyloid-beta-peptide cytotoxicity by competitive inhibition at a common phosphatidylserine interaction site

Amyloid-beta-protein (betaA/4, AbetaP) accumulates in the brains of patients with Alzheimer's disease (AD), regardless of genetic etiology, and is thought to be the toxic principle responsible for neuronal cell death. The varepsilon4 allele of apoE has been linked closely to earlier onset of AD and increased deposition of the amyloid peptide, regardless of the clinical status of AD, while the apoE varepsilon2 allele is generally protective. We have previously hypothesized that the cell target for amyloid peptide might be the apoptotic signal molecule phosphatidylserine (PS). We report here that annexin 5, a specific ligand for PS, not only blocks amyloid peptide AbetaP[1-40] cytotoxicity, but competitively inhibits AbetaP[1-40]-dependent aggregation of PS liposomes. In addition, we find that apoE2, but not apoE4, can not only perform the same protective effect on cells exposed to AbetaP[1-40], but can also competitively inhibit PS liposome aggregation and fusion by the amyloid peptide. Altogether, the in vivo and in vitro results reported here provide fundamental insight to the process by which amyloid targets specific neurons for destruction, and suggest that PS may be a surface "receptor" site for AbetaP binding. These results also provide a biochemical mechanism by which the apoE varepsilon2 allele, but not apoE varepsilon4, can be protective towards the incidence and progression of Alzheimer's disease.     

Cu（Ⅱ） Potentiation of Alzheimer Aβ1-40 Cytotoxicity and Transition on its Secondary Structure

Mounting evidence has shown that dyshomeostasis of the redox-active biometals such as Cuand Fe can lead to oxidative stress,which plays a key role in the neuropathology of Alzheimer's disease(AD).Here we demonstrate that with the formation of Cu(Ⅱ)·Aβ1-40 complexes,copper markedly potentiatesthe neurotoxicity exhibited by β-amyloid peptide (Aβ).A greater amount of hydrogen peroxide was releasedwhen Cu(Ⅱ)·Aβ1-40 complexes was added to the xanthine oxidase/xanthine system detected by potassiumiodide spectrophotometry.Copper bound to Aβ1-40 was observed by electron paramagnetic resonance(EPR) spectroscopy.Circular dichroism (CD) studies indicated that copper chelation could cause a structuraltransition of Aβ.The addition of copper to Aβ introduced an increase on β-sheet as well as α-helix,whichmay be responsible for the aggregation of Aβ.We hypothesized that Aβ aggregation induced by copper maybe responsible for local injury in AD.The interaction between Cu~(2 ) and Aβ also provides a possible mechanismfor the enrichment of metal ions in amyloid plaques in the AD brain.     

The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer’s Disease

There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer’s disease (AD), perhaps even before amyloid-β accumulation or brain atrophy. This evidence, consistent with the vascular hypothesis of AD, implicates cerebral blood flow (CBF) in the pathogenesis of AD and suggests its utility as a biomarker of preclinical AD. The extended preclinical phase of AD holds particular significance for disease modification, as treatment would likely be most effective in this early asymptomatic stage of disease. This highlights the importance of identifying reliable and accurate biomarkers of AD that can differentiate normal aging from preclinical AD prior to clinical symptom manifestation. Cerebral perfusion, as measured by arterial spin labeling magnetic resonance imaging (ASL-MRI), has been shown to distinguish between normal controls and adults with AD. In addition to demonstrating diagnostic utility, CBF has shown usefulness as a tool for identifying those who are at risk for AD and for predicting subtle cognitive decline and conversion to mild cognitive impairment and AD. Taken together, this evidence not only implicates CBF as a useful biomarker for tracking disease severity and progression, but also suggests that ASL-measured CBF may be useful for identifying candidates for future AD treatment trials, especially in the preclinical, asymptomatic phases of the disease.