Islet amyloid polypeptide & amyloid beta peptide roles in Alzheimer’s disease: two triggers,one disease

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions worldwide. Due to population ageing, the incidence of AD is increasing. AD patients develop cognitive decline and dementia, features for which is known, requiring permanent care. This poses a major socio-economic burden on healthcare systems as AD patients’ relatives and healthcare workers are forced to cope with rising numbers of affected people. Despite recent advances, AD pathological mechanisms are not fully understood. Nevertheless, it is clear that the amyloid beta (Aβ) peptide, which forms amyloid plaques in AD patients’ brains, plays a key role. Type 2 diabetes, the most common form of diabetes, affects hundreds of million people globally. Islet amyloid polypeptide (IAPP) is a hormone co-produced and secreted with insulin in pancreatic β-cells, with a key role in diabetes, as it helps regulate glucose levels and control adiposity and satiation. Similarly to Aβ, IAPP is very amyloidogenic, generating intracellular amyloid deposits that cause β-cell dysfunction and death. It is now clear that IAPP can also have a pathological role in AD, decreasing cognitive function. IAPP harms the blood-brain barrier, directly interacts and co-deposits with Aβ, promoting diabetes-associated dementia. IAPP can cause a metabolic dysfunction in the brain, leading to other diabetes-related forms of AD. Thus, here we discuss IAPP association with diabetes, Aβ and dementia, in the context of what we designate a “diabetes brain phenotype” AD hypothesis. Such approach helps to set a conceptual framework for future IAPP-based drugs against AD.     

β-amyloid Peptides and Amyloid Plaques in Alzheimer’s Disease

Many lines of evidence support that β-amyloid (Aβ) peptides play an important role in Alzheimer’s disease (AD), the most common cause of dementia. But despite much effort the molecular mechanisms of how Aβ contributes to AD remain unclear. While Aβ is generated from its precursor protein throughout life, the peptide is best known as the main component of amyloid plaques, the neuropathological hallmark of AD. Reduction in Aβ has been the major target of recent experimental therapies against AD. Unfortunately, human clinical trials targeting Aβ have not shown the hoped-for benefits. Thus, doubts have been growing about the role of Aβ as a therapeutic target. Here we review evidence supporting the involvement of Aβ in AD, highlight the importance of differentiating between various forms of Aβ, and suggest that a better understanding of Aβ’s precise pathophysiological role in the disease is important for correctly targeting it for potential future therapy.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-014-0313-y) contains supplementary material, which is available to authorized users.Key Words: Dementia, Alzheimer’s disease, amyloid precursor protein, amyloid, therapy     

Tau and transgenic animal models

Advances in genetics and transgenic approaches have a continuous impact on our understanding of Alzheimer’s disease (AD) and related disorders, especially as aspects of the histopathology and neurodegeneration can be reproduced in animal models. AD is characterized by extracellular Aβ peptide-containing plaques and neurofibrillary aggregates of hyperphosphorylated isoforms of microtubule-associated protein tau. A causal link between Aβ production, neurodegeneration and dementia has been established with the identification of familial forms of AD which are linked to mutations in the amyloid precursor protein APP, from which the Aβ peptide is derived by proteolysis. No mutations have been identified in the tau gene in AD until today. Tau filament formation, in the absence of Aβ production, is also a feature of several additional neurodegenerative diseases including progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The identification of mutations in the tau gene which are linked to FTDP-17 established that dysfunction of tau can, as well as Aβ formation, lead to neurodegeneration and dementia. In this review, newly recognized cellular functions of tau, and the neuropathology and clinical syndrome of FTDP-17 will be presented, as well as recent advances that have been achieved in studies of transgenic mice expressing tau and AD-related kinases and phosphatases. These models link neurofibrillary lesion formation to neuronal loss, provide an in vivo model in which therapies can be assessed, and may contribute to determine the relationship between Aβ production and tau pathology.     

Network interdigitations of Tau and amyloid‐beta deposits define cognitive levels in aging

Amyloid‐beta (Aβ) plaques and tau neurofibrillary tangles are pathological hallmarks of Alzheimer''s disease (AD); their contribution to neurodegeneration and clinical manifestations are critical in understanding preclinical AD. At present, the mechanisms related to Aβ and tau pathogenesis leading to cognitive decline in older adults remain largely unknown. Here, we examined graph theory‐based positron emission tomography (PET) analytical approaches, within and between tau and Aβ PET modalities, and tested the effects on cognitive changes in cognitively normal older adults (CN). Particularly, we focused on the network interdigitations of Aβ and tau deposits, along with cognitive test scores in CN at both baseline and 2‐year follow‐up (FU). We found highly significant Aβ‐tau network integrations in AD vulnerable areas, as well as significant associations between those Aβ‐tau interdigitations and general cognitive impairment in CN at baseline and FU. Our findings suggest a distinctive contribution of interlinking network relationships between Aβ and tau deposits in heteromodal areas of the human brain. They support a network‐based interaction between Aβ and tau accumulations as a key factor for cognitive deterioration in CN prior to dementia.     

An amyloid-β protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease

Human genetics link Alzheimer's disease pathogenesis to excessive accumulation of amyloid-β (Aβ) in brain, but the symptoms do not correlate with senile plaque burden. Since soluble Aβ aggregates can cause synaptic dysfunctions and memory deficits, these species could contribute to neuronal dysfunction and dementia. Here we explored selective targeting of large soluble aggregates, Aβ protofibrils, as a new immunotherapeutic strategy. The highly protofibril-selective monoclonal antibody mAb158 inhibited in vitro fibril formation and protected cells from Aβ protofibril-induced toxicity. When the mAb158 antibody was administered for 4 months to plaque-bearing transgenic mice with both the Arctic and Swedish mutations (tg-ArcSwe), Aβ protofibril levels were lowered while measures of insoluble Aβ were unaffected. In contrast, when treatment began before the appearance of senile plaques, amyloid deposition was prevented and Aβ protofibril levels diminished. Therapeutic intervention with mAb158 was however not proven functionally beneficial, since place learning depended neither on treatment nor transgenicity. Our findings suggest that Aβ protofibrils can be selectively cleared with immunotherapy in an animal model that display highly insoluble Aβ deposits, similar to those of Alzheimer's disease brain.     

Ruthenium Red Colorimetric and Birefringent Staining of Amyloid-β Aggregates in Vitro and in Tg2576 Mice

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Glutamate system,amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

Alzheimer disease is the most prevalent form of dementia globally and is characterized premortem by a gradual memory loss and deterioration of higher cognitive functions and postmortem by neuritic plaques containing amyloid β peptide and neurofibrillary tangles containing phospho-tau protein. Glutamate is the most abundant neurotransmitter in the brain and is essential to memory formation through processes such as long-term potentiation and so might be pivotal to Alzheimer disease progression. This review discusses how the glutamatergic system is impaired in Alzheimer disease and how interactions of amyloid β and glutamate influence synaptic function, tau phosphorylation and neurodegeneration. Interestingly, glutamate not only influences amyloid β production, but also amyloid β can alter the levels of glutamate at the synapse, indicating that small changes in the concentrations of both molecules could influence Alzheimer disease progression. Finally, we describe how the glutamate receptor antagonist, memantine, has been used in the treatment of individuals with Alzheimer disease and discuss its effectiveness.     

Promising Blood Biomarkers for Clinical Use in Alzheimer’s Disease: A Focused Update

Alzheimer’s disease (AD) is the most-common cause of neurodegenerative dementia, and it is characterized by abnormal amyloid and tau accumulation, which indicates neurodegeneration. AD has mostly been diagnosed clinically. However, ligand-specific positron emission tomography (PET) imaging, such as amyloid PET, and cerebrospinal fluid (CSF) biomarkers are needed to accurately diagnose AD, since they supplement the shortcomings of clinical diagnoses. Using biomarkers that represent the pathology of AD is essential (particularly when disease-modifying treatment is available) to identify the corresponding pathology of targeted therapy and for monitoring the treatment response. Although imaging and CSF biomarkers are useful, their widespread use is restricted by their high cost and the discomfort during the lumbar puncture, respectively. Recent advances in AD blood biomarkers shed light on their future use for clinical purposes. The amyloid β (Aβ)42/Aβ40 ratio and the concentrations of phosphorylated tau at threonine 181 and at threonine 217, and of neurofilament light in the blood were found to represent the pathology of Aβ, tau, and neurodegeneration in the brain when using automatic electrochemiluminescence technologies, single-molecule arrays, immunoprecipitation coupled with mass spectrometry, etc. These blood biomarkers are imminently expected to be incorporated into clinical practice to predict, diagnose, and determine the stage of AD. In this review we focus on advancements in the measurement technologies for blood biomarkers and the promising biomarkers that are approaching clinical application. We also discuss the current limitations, the needed further investigations, and the perspectives on their use.     

Benzothiazole Aniline Tetra(ethylene glycol) and 3-Amino-1,2,4-triazole Inhibit Neuroprotection against Amyloid Peptides by Catalase Overexpression in Vitro

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DNA vaccines targeting amyloid-β oligomer ameliorate cognitive deficits of aged APP/PS1/tau triple-transgenic mouse models of Alzheimer’s disease

The amyloid-β (Aβ) oligomer, rather than the Aβ monomer, is considered to be the primary initiator of Alzheimer’s disease. It was hypothesized that p(Aβ3–10)10-MT, the recombinant Aβ3–10 gene vaccine of the Aβ oligomer has the potential to treat Alzheimer’s disease. In this study, we intramuscularly injected the p(Aβ3–10)10-MT vaccine into the left hindlimb of APP/PS1/tau triple-transgenic mice, which are a model for Alzheimer’s disease. Our results showed that the p(Aβ3–10)10-MT vaccine effectively reduced Aβ oligomer levels and plaque deposition in the cerebral cortex and hippocampus, decreased the levels tau protein variants, reduced synaptic loss, protected synaptic function, reduced neuron loss, and ameliorated memory impairment without causing any cerebral hemorrhaging. Therefore, this novel DNA vaccine, which is safe and highly effective in mouse models of Alzheimer’s disease, holds a lot of promise for the treatment of Alzheimer’s disease in humans.     

Cerebrovascular phenotypes in mouse models of Alzheimer’s disease

Alzheimer’s disease (AD) is a devastating neurological degenerative disorder and is the most common cause of dementia in the elderly. Clinically, AD manifests with memory and cognitive decline associated with deposition of hallmark amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs). Although the mechanisms underlying AD remains unclear, two hypotheses have been proposed. The established amyloid hypothesis states that Aβ accumulation is the basis of AD and leads to formation of NFTs. In contrast, the two-hit vascular hypothesis suggests that early vascular damage leads to increased accumulation of Aβ deposits in the brain. Multiple studies have reported significant morphological changes of the cerebrovasculature which can result in severe functional deficits. In this review, we delve into known structural and functional vascular alterations in various mouse models of AD and the cellular and molecular constituents that influence these changes to further disease progression. Many studies shed light on the direct impact of Aβ on the cerebrovasculature and how it is disrupted during the progression of AD. However, more research directed towards an improved understanding of how the cerebrovasculature is modified over the time course of AD is needed prior to developing future interventional strategies.     

Apolipoprotein E deposition and astrogliosis are associated with maturation of β-amyloid plaques in βAPPswe transgenic mouse: Implications for the pathogenesis of Alzheimer’s disease

A transgenic mouse expressing the human β-amyloid precursor protein with the ‘Swedish’ mutation, Tg2576, was used to investigate the mechanism of β-amyloid (Aβ) deposition. Previously, we have reported that the major species of Aβ in the amyloid plaques of Tg2576 mice are Aβ_1-40 and Aβ_1-42. Moreover, Aβ_1-42 deposition precedes Aβ_1-40 deposition, while Aβ_1-40 accumulates in the central part of the plaques later in the pathogenic process. Those data indicate that Aβ deposits in Tg2576 mice have similar characteristics to those in Alzheimer’s disease. In the present study, to understand more fully the amyloid deposition mechanism implicating Alzheimer’s disease pathogenesis, we examined immunohistochemically the distributions of apolipoprotein E (apoE) and Aβ in amyloid plaques of aged Tg2576 mouse brains. Our findings suggest that Aβ_1-42 deposition precedes apoE deposition, and that Aβ_1-40 deposition follows apoE deposition during plaque maturation. We next examined the relationship between apoE and astrogliosis associated with amyloid plaques using a double-immunofluorescence method. Extracellular apoE deposits were always associated with reactive astrocytes whose processes showed enhancement of apoE-immunoreactivity. Taken together, the characteristics of amyloid plaques in Tg2576 mice are similar to those in Alzheimer’s disease with respect to apoE and astrogliosis. Furthermore, apoE deposition and astrogliosis may be necessary for amyloid plaque maturation.     

Effect of the English Familial Disease Mutation (H6R) on the Monomers and Dimers of Aβ40 and Aβ42

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Immunodominant epitope and properties of pyroglutamate-modified Aβ-specific antibodies produced in rabbits

N-truncated and N-modified forms of amyloid beta (Aβ) peptide are found in diffused and dense core plaques in Alzheimer's disease (AD) and Down's syndrome patients as well as transgenic mouse models of AD. Although the pathological significance of these shortened forms Aβ is not completely understood, previous studies have demonstrated that these peptides are significantly more resistant to degradation, aggregate more rapidly in vitro and exhibit similar or, in some cases, increased toxicity in hippocampal neuronal cultures compared to the full length peptides. In the present study we further investigated the mechanisms of toxicity of one of the most abundant N-truncated/modified Aβ peptide bearing amino-terminal pyroglutamate at position 3 (AβN3(pE)). We demonstrated that AβN3(pE) oligomers induce phosphatidyl serine externalization and membrane damage in SH-SY5Y cells. Also, we produced AβN3(pE)-specific polyclonal antibodies in rabbit and identified an immunodominant epitope recognized by anti-AβN3(pE) antibodies. Our results are important for developing new immunotherapeutic compounds specifically targeting AβN3(pE) aggregates since the most commonly used immunogens in the majority of vaccines for AD have been shown to induce antibodies that recognize the N-terminal immunodominant epitope (EFRH) of the full length Aβ, which is absent in N-amino truncated peptides.     

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

l-tryptophan (NQTrp) molecule was reported to alter Aβ self-assembly and reduce toxicity. Though nuclear magnetic resonance experiments and various simulations provided atomic information about the interaction of NQTrp with Aβ peptides spanning the regions of residues 12–28 and 17–42, none of these studies were conducted on the full-length Aβ1–42 peptide. To this end, we performed extensive atomistic replica exchange molecular dynamics simulations of Aβ1–42 dimer with two NQTrp molecules in explicit solvent, by using a force field known to fold diverse proteins correctly. The interactions between NQTrp and Aβ1–42, which change the Aβ interface by reducing most of the intermolecular contacts, are found to be very dynamic and multiple, leading to many transient binding sites. The most favorable binding residues are Arg5, Asp7, Tyr10, His13, Lys16, Lys18, Phe19/Phe20, and Leu34/Met35, providing therefore a completely different picture from in vitro and in silico experiments with NQTrp with shorter Aβ fragments. Importantly, the 10 hot residues that we identified explain the beneficial effect of NQTrp in reducing both the level of Aβ1–42 aggregation and toxicity. Our results also indicate that there is room to design more efficient drugs targeting Aβ1–42 dimer against AD.     

Microvessel occlusions alter amyloid-beta plaque morphology in a mouse model of Alzheimer’s disease

Vascular dysfunction is correlated to the incidence and severity of Alzheimer’s disease. In a mouse model of Alzheimer’s disease (APP/PS1) using in vivo, time-lapse, multiphoton microscopy, we found that occlusions of the microvasculature alter amyloid-beta (Aβ) plaques. We used several models of vascular injury that varied in severity. Femtosecond laser-induced occlusions in single capillaries generated a transient increase in small, cell-sized, Aβ deposits visualized with methoxy-X04, a label of fibrillar Aβ. After occlusions of penetrating arterioles, some plaques changed morphology, while others disappeared, and some new plaques appeared within a week after the lesion. Antibody labeling of Aβ revealed a transient increase in non-fibrillar Aβ one day after the occlusion that coincided with the disappearance of methoxy-X04-labeled plaques. Four days after the lesion, anti-Aβ labeling decreased and only remained in patches unlabeled by methoxy-X04 near microglia. Histology in two additional models, sparse embolic occlusions from intracarotid injections of beads and infarction from photothrombosis, demonstrated increased labeling intensity in plaques after injury. These results suggest that microvascular lesions can alter the deposition and clearance of Aβ and confirm that Aβ plaques are dynamic structures, complicating the interpretation of plaque burden as a marker of Alzheimer’s disease progression.     

Tetrahydrohyperforin prevents cognitive deficit,Aβ deposition,tau phosphorylation and synaptotoxicity in the APPswe/PSEN1ΔE9 model of Alzheimer's disease: a possible effect on APP processing

Alzheimer''s disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-β peptide (Aβ) accumulation and synaptic alterations. Previous studies indicated that hyperforin, a component of the St John''s Wort, prevents Aβ neurotoxicity and some behavioral impairments in a rat model of AD. In this study we examined the ability of tetrahydrohyperforin (IDN5607), a stable hyperforin derivative, to prevent the cognitive deficit and synaptic impairment in an in vivo model of AD. In double transgenic APPswe/PSEN1ΔE9 mice, IDN5706 improves memory and prevents the impairment of synaptic plasticity in a dose-dependent manner, inducing a recovery of long-term potentiation. In agreement with these findings, IDN5706 prevented the decrease in synaptic proteins in hippocampus and cortex. In addition, decreased levels of tau hyperphosphorylation, astrogliosis, and total fibrillar and oligomeric forms of Aβ were determined in double transgenic mice treated with IDN5706. In cultured cells, IDN5706 decreased the proteolytic processing of the amyloid precursor protein that leads to Aβ peptide generation. These findings indicate that IDN5706 ameliorates AD neuropathology and could be considered of therapeutic relevance in AD treatment.     

Unbalanced Regulation of α7 nAChRs by Ly6h and NACHO Contributes to Neurotoxicity in Alzheimer's Disease

α7 nicotinic acetylcholine receptors (nAChRs) are widely expressed in the brain where they promote fast cholinergic synaptic transmission and serve important neuromodulatory functions. However, their high permeability to Ca²⁺ also predisposes them to contribute to disease states. Here, using transfected HEK-tsa cells and primary cultured hippocampal neurons from male and female rats, we demonstrate that two proteins called Ly6h and NACHO compete for access to α7 subunits, operating together but in opposition to maintain α7 assembly and activity within a narrow range that is optimal for neuronal function and viability. Using mixed gender human temporal cortex and cultured hippocampal neurons from rats we further show that this balance is perturbed during Alzheimer''s disease (AD) because of amyloid β (Aβ)-driven reduction in Ly6h, with severe reduction leading to increased phosphorylated tau and α7-mediated neurotoxicity. Ly6h release into human CSF is also correlated with AD severity. Thus, Ly6h links cholinergic signaling, Aβ and phosphorylated tau and may serve as a novel marker for AD progression.SIGNIFICANCE STATEMENT One of the earliest and most persistent hypotheses regarding Alzheimer''s disease (AD) attributes cognitive impairment to loss of cholinergic signaling. More recently, interest has focused on crucial roles for amyloid β (Aβ) and phosphorylated tau in Alzheimer''s pathogenesis. Here, we demonstrate that these elements are linked by Ly6h and its counterpart, NACHO, functioning in opposition to maintain assembly of nicotinic acetylcholine receptors (nAChRs) within the physiological range. Our data suggests that Aβ shifts the balance away from Ly6h and toward NACHO, resulting in increased assembly of Ca²⁺-permeable nAChRs and thus a conversion of basal cholinergic to neurotoxic signaling.