RESUMEN
Defects in interleukin-1ß (IL-1ß)-mediated cellular responses contribute to Alzheimer's disease (AD). To decipher the mechanism associated with its pathogenesis, we investigated the molecular events associated with the termination of IL-1ß inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1ß receptor-1 (IL-1R1). We first show that TOM1 steady-state levels are reduced in human AD hippocampi and in the brain of an AD mouse model versus respective controls. Experimentally reducing TOM1 affected microglia activity, substantially increased amyloid-beta levels, and impaired cognition, whereas enhancing its levels was therapeutic. These data show that reparation of the TOM1-signaling pathway represents a therapeutic target for brain inflammatory disorders such as AD. A better understanding of the age-related changes in the immune system will allow us to craft therapies to limit detrimental aspects of inflammation, with the broader purpose of sharply reducing the number of people afflicted by AD.
RESUMEN
Alzheimer's disease (AD) is a progressive neurological disorder that impairs memory and other cognitive functions in the elderly. The social and financial impacts of AD are overwhelming and are escalating exponentially as a result of population aging. Therefore, identifying AD-related risk factors and the development of more efficacious therapeutic approaches are critical to cure this neurological disorder. Current epidemiological evidence indicates that life experiences, including chronic stress, are a risk for AD. However, it is unknown if short-term stress, lasting for hours, influences the onset or progression of AD. Here, we determined the effect of short-term, multi-modal 'modern life-like' stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aß levels by augmenting AßPP processing. Thus, short-term stress simulating modern-life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers. Epidemiological evidence indicates that life experiences, including chronic stress, are a risk for Alzheimer disease (AD). However, it is unknown if short stress in the range of hours influences the onset or progression of AD. Here, we determined the effect of short, multi-modal 'modern-lifelike'stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aß levels by augmenting AßPP processing. Thus, short stress simulating modern-life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers.
Asunto(s)
Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Ruido/efectos adversos , Estrés Psicológico/complicaciones , Vibración/efectos adversos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Animales , Células Cultivadas , Corticosterona/sangre , Hormona Liberadora de Corticotropina/fisiología , Dendritas/metabolismo , Dendritas/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Emociones , Conducta Exploratoria , Glucocorticoides/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Plasticidad Neuronal , Reconocimiento en Psicología , Estrés Psicológico/metabolismo , Estrés Psicológico/patología , Sinapsis/patología , Proteínas tau/genéticaRESUMEN
Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, affecting over 35 million people worldwide. Pathologically, AD is characterized by the progressive accumulation of ß-amyloid (Aß) plaques and neurofibrillary tangles within the brain. Together, these pathologies lead to marked neuronal and synaptic loss and corresponding impairments in cognition. Current treatments, and recent clinical trials, have failed to modify the clinical course of AD; thus, the development of novel and innovative therapies is urgently needed. Over the last decade, the potential use of stem cells to treat cognitive impairment has received growing attention. Specifically, neural stem cell transplantation as a treatment for AD offers a novel approach with tremendous therapeutic potential. We previously reported that intrahippocampal transplantation of murine neural stem cells (mNSCs) can enhance synaptogenesis and improve cognition in 3xTg-AD mice and the CaM/Tet-DT(A) model of hippocampal neuronal loss. These promising findings prompted us to examine a human neural stem cell population, HuCNS-SC, which has already been clinically tested for other neurodegenerative disorders. In this study, we provide the first evidence that transplantation of research grade HuCNS-SCs can improve cognition in two complementary models of neurodegeneration. We also demonstrate that HuCNS-SC cells can migrate and differentiate into immature neurons and glia and significantly increase synaptic and growth-associated markers in both 3xTg-AD and CaM/Tet-DTA mice. Interestingly, improvements in aged 3xTg-AD mice were not associated with altered Aß or tau pathology. Rather, our findings suggest that human NSC transplantation improves cognition by enhancing endogenous synaptogenesis. Taken together, our data provide the first preclinical evidence that human NSC transplantation could be a safe and effective therapeutic approach for treating AD.
Asunto(s)
Enfermedad de Alzheimer , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/cirugía , Células-Madre Neurales/trasplante , Neuronas/patología , Sinapsis/fisiología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Muerte Celular/fisiología , Diferenciación Celular/genética , Movimiento Celular/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/patología , Humanos , Aprendizaje por Laberinto , Ratones , Ratones Transgénicos , Mutación/genética , Células-Madre Neurales/fisiología , Neurogénesis/genética , Proteínas tau/genéticaRESUMEN
Alzheimer's disease (AD) is an age-related dementia, characterized by amyloid plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss in the brain. Components of the complement system, known to produce a local inflammatory reaction, are associated with the plaques and tangles in AD brain, and thus a role for complement-mediated inflammation in the acceleration or progression of disease has been proposed. A complement activation product, C5a, is known to recruit and activate microglia and astrocytes in vitro by activation of a G protein-coupled cell-surface C5aR. Here, oral delivery of a cyclic hexapeptide C5a receptor antagonist (PMX205) for 2-3 mo resulted in substantial reduction of pathological markers such as fibrillar amyloid deposits (49-62%) and activated glia (42-68%) in two mouse models of AD. The reduction in pathology was correlated with improvements in a passive avoidance behavioral task in Tg2576 mice. In 3xTg mice, PMX205 also significantly reduced hyperphosphorylated tau (69%). These data provide the first evidence that inhibition of a proinflammatory receptor-mediated function of the complement cascade (i.e., C5aR) can interfere with neuroinflammation and neurodegeneration in AD rodent models, suggesting a novel therapeutic target for reducing pathology and improving cognitive function in human AD patients.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Degeneración Nerviosa/prevención & control , Péptidos Cíclicos/farmacología , Receptor de Anafilatoxina C5a/antagonistas & inhibidores , Receptores de Complemento/antagonistas & inhibidores , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Animales , Modelos Animales de Enfermedad , Inflamación/prevención & control , Ratones , Ovillos Neurofibrilares/efectos de los fármacos , Ovillos Neurofibrilares/patología , Neuroglía/patología , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/uso terapéutico , Trastornos de la Personalidad/prevención & control , Placa Amiloide/efectos de los fármacos , Placa Amiloide/patologíaRESUMEN
The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aß under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aß sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aß sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAß expression, rescues cognition and reduces the formation of PAS granules.
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Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Mutación , Plasticidad Neuronal/fisiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Plasticidad Neuronal/genéticaRESUMEN
Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by the accumulation of amyloid-beta protein and neuronal loss, is the leading cause of age-related dementia in the world today. The disease is also associated with neuroinflammation, robust activation of astrocytes and microglia, and evidence of activation of the complement system, localized with both fibrillar amyloid-beta (fAbeta) plaques and tangles. The observations are consistent with a complement-dependent component of AD progression. We have previously shown that inhibition of the major complement receptor for C5a (CD88) with the antagonist PMX205 results in a significant reduction in pathology in two mouse models of AD. To further characterize the role of complement in AD-related neuroinflammation, we examined the age- and disease-associated expression of CD88 in brain of transgenic mouse models of AD and the influence of PMX205 on the presence of various complement activation products using flow cytometry, western blot, and immunohistochemistry. CD88 was found to be up-regulated in microglia, in the immediate vicinity of amyloid plaques. While thioflavine plaque load and glial recruitment is significantly reduced after treatment with PMX205, C1q remains co-localized with fAbeta plaques and C3 is still expressed by the recruited astrocytes. Thus, with PMX205, potentially beneficial activities of these early complement components may remain intact, while detrimental activities resulting from C5a-CD88 interaction are inhibited. This further supports the targeted inhibition of specific complement mediated activities as an approach for AD therapy.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Regulación de la Expresión Génica/genética , Microglía/metabolismo , Receptor de Anafilatoxina C5a/metabolismo , Estadística como Asunto/métodos , Factores de Edad , Precursor de Proteína beta-Amiloide/genética , Animales , Animales Recién Nacidos , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Citometría de Flujo/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación/genética , Neuronas/metabolismo , Péptidos Cíclicos/farmacología , Receptor de Anafilatoxina C5a/antagonistas & inhibidores , Receptor de Anafilatoxina C5a/deficienciaRESUMEN
Evidence has been accumulating for a role of inflammation in the development of Alzheimer's disease (AD), a progressive neurodegenerative disorder causing a common form of dementia in the elderly. C1q, part of the initiation component of the classical complement pathway (CCP), is associated with beta-sheet, fibrillar amyloid plaques in AD brain. In vitro, beta-amyloid peptide in fibrillar beta-sheet conformation (fAbeta) can activate CCP via interaction of specific negatively charged amino acids of the beta-amyloid fibril with human C1q. Previous results using peptide inhibitors led to the hypothesis that a highly positively charged domain consisting of three arginine residues, such as that present in the N-terminal collagen-like region of the human C1q A chain, may be critical for the activation event. However, mouse C1q A chain lacks two of the three arginines in the corresponding C1q A chain collagen-like region. To test the hypothesis that this divergent activation domain results in a weaker C' activation and thus may contribute to the lower neuronal loss observed in transgenic mouse models of AD, a partially humanized C1q A chain knock-in mouse was generated. The mouse C1q A chain gene was modified by homologous recombination to replace 4 residues in the 13-20 amino acid region to mimic the corresponding sequence from human A chain. No significant differences in the expression of C1q were found in sera from mice homozygous for the humanized C1q A chain compared to littermate wild type mice. Two distinct C1 activation assays demonstrated that activation by fAbeta was not significantly different in the homozygous humanized C1q A chain mice. Activation of C1 by DNA, previously hypothesized to interact with this C1q A chain arginine-rich sequence was also not significantly different in the knock-in mouse. Molecular modeling based on the published crystal structure of human C1q B chain globular head and a beta-sheet model for fibrillar amyloid suggests an alternative arginine ladder in the globular head domain may provide the functional C1 activating interaction domains. The humanized C1q mouse generated here should provide a better animal model for assessing the mechanisms of C1 activation and the contribution of C1q to human health and disease.
Asunto(s)
Péptidos beta-Amiloides/farmacología , Activación de Complemento/efectos de los fármacos , Complemento C1q/genética , Complemento C1q/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos/inmunología , Complemento C1q/química , Complemento C1q/aislamiento & purificación , ADN , Hemólisis/efectos de los fármacos , Humanos , Ratones , Modelos Moleculares , Datos de Secuencia MolecularRESUMEN
Diabetes mellitus (DM) is one of the most devastating diseases that currently affects the aging population. Recent evidence indicates that DM is a risk factor for many brain disorders, due to its direct effects on cognition. New findings have shown that the microtubule-associated protein tau is pathologically processed in DM; however, it remains unknown whether pathological tau modifications play a central role in the cognitive deficits associated with DM. To address this question, we used a gain-of-function and loss-of-function approach to modulate tau levels in type 1 diabetes (T1DM) and type 2 diabetes (T2DM) mouse models. Our study demonstrates that tau differentially contributes to cognitive and synaptic deficits induced by DM. On one hand, overexpressing wild-type human tau further exacerbates cognitive and synaptic impairments induced by T1DM, as human tau mice treated under T1DM conditions show robust deficits in learning and memory processes. On the other hand, neither a reduction nor increase in tau levels affects cognition in T2DM mice. Together, these results shine new light onto the different molecular mechanisms that underlie the cognitive and synaptic impairments associated with T1DM and T2DM.
Asunto(s)
Disfunción Cognitiva/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2 , Modelos Animales de Enfermedad , Sinapsis/metabolismo , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Diabetes Mellitus Tipo 1/inducido químicamente , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Ratones Transgénicos , EstreptozocinaRESUMEN
Alzheimer's disease (AD) is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. New evidences indicate that AD is conceptualized as a disease of synaptic failure, although the molecular and cellular mechanisms underlying these defects remain to be elucidated. Determining the timing and nature of the early synaptic deficits is critical for understanding the progression of the disease and for identifying effective targets for therapeutic intervention. Using single-synapse functional and morphological analyses, we find that AMPA signaling, which mediates fast glutamatergic synaptic transmission in the central nervous system (CNS), is compromised early in the disease course in an AD mouse model. The decline in AMPA signaling is associated with changes in actin cytoskeleton integrity, which alters the number and the structure of dendritic spines. AMPA dysfunction and spine alteration correlate with the presence of soluble but not insoluble Aß and tau species. In particular, we demonstrate that these synaptic impairments can be mitigated by Aß immunotherapy. Together, our data suggest that alterations in AMPA signaling and cytoskeletal processes occur early in AD. Most important, these deficits are prevented by Aß immunotherapy, suggesting that existing therapies, if administered earlier, could confer functional benefits.
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Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Citoesqueleto/metabolismo , Modelos Animales de Enfermedad , Transducción de Señal , Transmisión Sináptica , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Alzheimer's disease is a neurodegenerative disease associated with progressive memory and cognitive decline. Previous studies have identified the benefits of cognitive enrichment on reducing disease pathology. Additionally, epidemiological and clinical data suggest that repeated exercise, and cognitive and social enrichment, can improve and/or delay the cognitive deficiencies associated with aging and neurodegenerative diseases. In the present study, 3xTg-AD mice were exposed to a rigorous training routine beginning at 3 months of age, which consisted of repeated training in the Morris water maze spatial recognition task every 3 months, ending at 18 months of age. At the conclusion of the final Morris water maze training session, animals subsequently underwent testing in another hippocampus-dependent spatial task, the Barnes maze task, and on the more cortical-dependent novel object recognition memory task. Our data show that periodic cognitive enrichment throughout aging, via multiple learning episodes in the Morris water maze task, can improve the memory performance of aged 3xTg-AD mice in a separate spatial recognition task, and in a preference memory task, when compared to naïve aged matched 3xTg-AD mice. Furthermore, we observed that the cognitive enrichment properties of Morris water maze exposer, was detectable in repeatedly trained animals as early as 6 months of age. These findings suggest early repeated cognitive enrichment can mitigate the diverse cognitive deficits observed in Alzheimer's disease.
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Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/terapia , Terapia Cognitivo-Conductual/métodos , Aprendizaje por Laberinto , Trastornos de la Memoria/fisiopatología , Trastornos de la Memoria/terapia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Memoria , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Transgénicos , Presenilina-1/genética , Presenilina-1/metabolismo , Resultado del TratamientoRESUMEN
The initiation of an inflammatory response is critical to the survival of an organism. However, when inflammation fails to reach resolution, a chronic inflammatory state may occur, potentially leading to bystander tissue damage. Accumulating evidence suggests that chronic inflammation contributes to the progression of Alzheimer's disease (AD), and identifying mechanisms to resolve the pro-inflammatory environment stimulated by AD pathology remains an area of active investigation. Previously, we found that treatment with the pro-resolving mediator aspirin-triggered lipoxin A4 (ATL), improved cognition, reduced Aß levels, and enhanced microglia phagocytic activity in Tg2576 transgenic AD mice. Here, we evaluated the effect of aging on brain lipoxin A4 (LXA4) levels using non-transgenic and 3xTg-AD mice. Additionally, we investigated the effect of ATL treatment on tau pathology in 3xTg-AD mice. We found that LXA4 levels are reduced with age, a pattern significantly more impacted in 3xTg-AD mice. Moreover, ATL delivery enhanced the cognitive performance of 3xTg-AD mice and reduced Aß levels, as well as decreased the levels of phosphorylated-tau (p-tau). The decrease in p-tau was due in part to an inhibition of the tau kinases GSK-3ß and p38 MAPK. In addition, microglial and astrocyte reactivity was inhibited by ATL treatment. Our results suggest that the inability to resolve the immune response during aging might be an important feature that contributes to AD pathology and cognitive deficits. Furthermore, we demonstrate that activation of LXA4 signaling could serve as a potential therapeutic target for AD-related inflammation and cognitive dysfunction.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Lipoxinas/farmacología , Microglía/metabolismo , Transducción de Señal/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Lipoxinas/metabolismo , Lipoxinas/uso terapéutico , Ratones , Ratones Transgénicos , Microglía/efectos de los fármacos , Fosforilación , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
Alzheimer's disease (AD) is a proteinopathy characterized by the accumulation of ß-amyloid (Aß) and tau. To date, clinical trials indicate that Aß immunotherapy does not improve cognition. Consequently, it is critical to modulate other aspects of AD pathology. As such, tau represents an excellent target, as its accumulation better correlates with cognitive impairment. To determine the effectiveness of targeting pathological tau, with Aß pathology present, we administered a single injection of AT8, or control antibody, into the hippocampus of aged 3xTg-AD mice. Extensive data indicates that phosphorylated Ser(202) and Thr(205) sites of tau (corresponding to the AT8 epitope) represent a pathologically relevant target for AD. We report that immunization with AT8 reduced somatodendritic tau load, p-tau immunoreactivity, and silver stained positive neurons, without affecting Aß pathology. We also discovered that tau pathology soon reemerges post-injection, possibly due to persistent Aß pathology. These studies provide evidence that targeting p-tau may represent an effective treatment strategy: potentially in conjunction with Aß immunotherapy.
Asunto(s)
Enfermedad de Alzheimer/terapia , Anticuerpos/uso terapéutico , Proteínas tau/inmunología , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Epítopos , Inmunoterapia , Ratones Transgénicos , Fosforilación , Proteínas tau/metabolismoRESUMEN
The complement system is a pivotal component of the innate immune system which protects the host from infection and injury. Complement proteins can be induced in all cell types within the central nervous system (CNS), where the pathway seems to play similar roles in host defense. Complement activation produces the C5 cleavage fragment C5a, a potent inflammatory mediator, which recruits and activates immune cells. The primary cellular receptor for C5a, the C5a receptor (CD88), has been reported to be on all CNS cells, including neurons and glia, suggesting a functional role for C5a in the CNS. A second receptor for C5a, the C5a-like receptor 2 (C5L2), is also expressed on these cells; however, little is currently known about its potential role in the CNS. The potent immune and inflammatory actions of complement activation are necessary for host defense. However, if over-activated, or left unchecked it promotes tissue injury and contributes to brain disease pathology. Thus, complement activation, and subsequent C5a generation, is thought to play a significant role in the progression of CNS disease. Paradoxically, complement may also exert a neuroprotective role in these diseases by aiding in the elimination of aggregated and toxic proteins and debris which are a principal hallmark of many of these diseases. This review will discuss the expression and known roles for complement in the CNS, with a particular focus on the pro-inflammatory end-product, C5a. The possible overarching role for C5a in diseases of the CNS is reviewed, and the therapeutic potential of blocking C5a/CD88 interaction is evaluated.
Asunto(s)
Sistema Nervioso Central/fisiología , Proteínas del Sistema Complemento/fisiología , Astrocitos/fisiología , Activación de Complemento/inmunología , Activación de Complemento/fisiología , Complemento C5a/metabolismo , Complemento C5a/fisiología , Proteínas del Sistema Complemento/genética , Proteínas del Sistema Complemento/inmunología , Humanos , Inmunidad Innata , Inflamación/inmunología , Inflamación/fisiopatología , Microglía/fisiología , Modelos Neurológicos , Neuronas/fisiología , Oligodendroglía/fisiología , Receptor de Anafilatoxina C5a/inmunología , Receptor de Anafilatoxina C5a/fisiologíaRESUMEN
The anaphylatoxin (AT) C3a, C5a and C5a-desArg are generally considered pro-inflammatory polypeptides generated after proteolytic cleavage of C3 and C5 in response to complement activation. Their well-appreciated effector functions include chemotaxis and activation of granulocytes, mast cells and macrophages. Recent evidence suggests that ATs are also generated locally within tissues by pathogen-, cell-, or contact system-derived proteases. This local generation of ATs is important for their pleiotropic biologic effects beyond inflammation. The ATs exert most of the biologic activities through ligation of three cognate receptors, i.e. the C3a receptor, the C5a receptor and the C5a receptor-like, C5L2. Here, we will discuss recent findings suggesting that ATs regulate cell apoptosis, lipid metabolism as well as innate and adaptive immune responses through their impact on antigen-presenting cells and T cells. As we will outline, such regulatory functions of ATs and their receptors play important roles in the pathogenesis of allergy, autoimmunity, neurodegenerative diseases, cancer and infections with intracellular pathogens.