RESUMEN
Early pathological upregulation of adenosine A2A receptors (A2ARs), one of the caffeine targets, by neurons is thought to be involved in the development of synaptic and memory deficits in Alzheimer's disease (AD) but mechanisms remain ill-defined. To tackle this question, we promoted a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice developing AD-like amyloidogenesis. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioural changes were not linked to major change in the development of amyloid pathology but rather associated with increased phosphorylated tau at neuritic plaques. Moreover, proteomic and transcriptomic analyses coupled with quantitative immunofluorescence studies indicated that neuronal upregulation of the receptor promoted both neuronal and non-neuronal autonomous alterations, i.e. enhanced neuroinflammatory response but also loss of excitatory synapses and impaired neuronal mitochondrial function, presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction, as seen in the brain of patients, contributes to amyloid-related pathogenesis and underscores the potential of A2AR as a relevant therapeutic target for mitigating cognitive impairments in this neurodegenerative disorder.
Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Trastornos de la Memoria , Ratones Transgénicos , Neuronas , Receptor de Adenosina A2A , Sinapsis , Animales , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/genética , Trastornos de la Memoria/patología , Ratones , Receptor de Adenosina A2A/metabolismo , Receptor de Adenosina A2A/genética , Sinapsis/metabolismo , Sinapsis/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Hipocampo/metabolismo , Hipocampo/patología , Presenilina-1/genética , Modelos Animales de Enfermedad , Placa Amiloide/patología , Placa Amiloide/metabolismo , Masculino , Ratones Endogámicos C57BLRESUMEN
Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment.
Asunto(s)
Antineoplásicos , Neuralgia , Animales , Ratones , Cisplatino/efectos adversos , Purinas/farmacología , Neuralgia/inducido químicamente , Receptor de Adenosina A2A , Antineoplásicos/efectos adversosRESUMEN
Due to the pathophysiological complexity of Alzheimer's disease, multitarget approaches able to mitigate several pathogenic mechanisms are of interest. Previous studies have pointed to the neuroprotective potential of Doxycycline (Dox), a safe and inexpensive second-generation tetracycline. Dox has been particularly reported to slow down aggregation of misfolded proteins but also to mitigate neuroinflammatory processes. Here, we have evaluated the pre-clinical potential of Dox in the APP/PS1 mouse model of amyloidogenesis. Dox was provided to APP/PS1 mice from the age of 8 months, when animals already exhibit amyloid pathology and memory deficits. Spatial memory was then evaluated from 9 to 10 months of age. Our data demonstrated that Dox moderately improved the spatial memory of APP/PS1 mice without exerting major effect on amyloid lesions. While Dox did not alleviate overall glial reactivity, we could evidence that it rather enhanced the amyloid-dependent upregulation of several neuroinflammatory markers such as CCL3 and CCL4. Finally, Dox exerted differentially regulated the levels of synaptic proteins in the hippocampus and the cortex of APP/PS1 mice. Overall, these observations support that chronic Dox delivery does not provide major pathophysiological improvements in the APP/PS1 mouse model.
Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Modelos Animales de Enfermedad , Doxiciclina/farmacología , Doxiciclina/uso terapéutico , Hipocampo/metabolismo , Ratones , Ratones Transgénicos , Presenilina-1/genética , Presenilina-1/metabolismoRESUMEN
Tau proteins aggregate into filaments in brain cells in Alzheimer's disease and related disorders referred to as tauopathies. Here, we used fragments of camelid heavy-chain-only antibodies (VHHs or single domain antibody fragments) targeting Tau as immuno-modulators of its pathologic seeding. A VHH issued from the screen against Tau of a synthetic phage-display library of humanized VHHs was selected for its capacity to bind Tau microtubule-binding domain, composing the core of Tau fibrils. This parent VHH was optimized to improve its biochemical properties and to act in the intra-cellular compartment, resulting in VHH Z70. VHH Z70 precisely binds the PHF6 sequence, known for its nucleation capacity, as shown by the crystal structure of the complex. VHH Z70 was more efficient than the parent VHH to inhibit in vitro Tau aggregation in heparin-induced assays. Expression of VHH Z70 in a cellular model of Tau seeding also decreased the aggregation-reporting fluorescence signal. Finally, intra-cellular expression of VHH Z70 in the brain of an established tauopathy mouse seeding model demonstrated its capacity to mitigate accumulation of pathological Tau. VHH Z70, by targeting Tau inside brain neurons, where most of the pathological Tau resides, provides an immunological tool to target the intra-cellular compartment in tauopathies.
Asunto(s)
Enfermedad de Alzheimer , Anticuerpos de Dominio Único , Tauopatías , Enfermedad de Alzheimer/metabolismo , Animales , Modelos Animales de Enfermedad , Ratones , Neuronas/metabolismo , Proteínas Represoras , Tauopatías/metabolismo , Proteínas tau/genéticaRESUMEN
Recent reports suggested a role for microtubules in double-strand-DNA break repair. We herein investigated the role of the microtubule-associated protein Tau in radio- and chemotherapy. Noticeably, a lowered expression of Tau in breast cancer cell lines resulted in a significant decrease in mouse-xenograft breast tumor volume after doxorubicin or X-ray treatments. Furthermore, the knockdown of Tau impaired the classical nonhomologous end-joining pathway and led to an improved cellular response to both bleomycin and X-rays. Investigating the mechanism of Tau's protective effect, we found that one of the main mediators of response to double-stranded breaks in DNA, the tumor suppressor p53-binding protein 1 (53BP1), is sequestered in the cytoplasm as a consequence of Tau downregulation. We demonstrated that Tau allows 53BP1 to translocate to the nucleus in response to DNA damage by chaperoning microtubule protein trafficking. Moreover, Tau knockdown chemo-sensitized cancer cells to drugs forming DNA adducts, such as cisplatin and oxaliplatin, and further suggested a general role of Tau in regulating the nuclear trafficking of DNA repair proteins. Altogether, these results suggest that Tau expression in cancer cells may be of interest as a molecular marker for response to DNA-damaging anti-cancer agents. Clinically targeting Tau could sensitize tumors to DNA-damaging treatments.
RESUMEN
Tauopathies are neurodegenerative diseases characterized by tau inclusions in brain cells. Seed-competent tau species have been suggested to spread from cell to cell in a stereotypical manner, indicating that this may involve a prion-like mechanism. Although the intercellular mechanisms of transfer are unclear, extracellular vesicles (EVs) could be potential shuttles. We assessed this in humans by preparing vesicles from fluids (brain-derived enriched EVs [BD-EVs]). These latter were isolated from different brain regions in various tauopathies, and their seeding potential was assessed in vitro and in vivo. We observed considerable heterogeneity among tauopathies and brain regions. The most striking evidence was coming mainly from Alzheimer's disease where the BD-EVs clearly contain pathological species that can induce tau lesions in vivo. The results support the hypothesis that BD-EVs participate in the prion-like propagation of tau pathology among tauopathies, and there may be implications for diagnostic and therapeutic strategies.
Asunto(s)
Enfermedad de Alzheimer , Vesículas Extracelulares , Tauopatías , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Tauopatías/genética , Tauopatías/patología , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
A major goal in diseases is identifying a potential therapeutic agent that is cost-effective and can remedy some, if not all, disease symptoms. In Alzheimer's disease (AD), aggregation of hyperphosphorylated tau protein is one of the neuropathological hallmarks, and Tau pathology correlates better with cognitive impairments in AD patients than amyloid-ß load, supporting a key role of tau-related mechanisms. Selenium is a non-metallic trace element that is incorporated in the brain into selenoproteins. Chronic treatment with sodium selenate, a non-toxic selenium compound, was recently reported to rescue behavioral phenotypes in tau mouse models. Here, we focused on the effects of chronic selenate application on synaptic transmission and synaptic plasticity in THY-Tau22 mice, a transgenic animal model of tauopathies. Three months with a supplement of sodium selenate in the drinking water (12 µg/ml) restored not only impaired neurocognitive functions but also rescued long-term depression (LTD), a major form of synaptic plasticity. Furthermore, selenate reduced the inactive demethylated catalytic subunit of protein phosphatase 2A (PP2A) in THY-Tau22 without affecting total PP2A.Our study provides evidence that chronic dietary selenate rescues functional synaptic deficits of tauopathy and identifies activation of PP2A as the putative mechanism.
RESUMEN
Alzheimer's disease (AD) is characterized by the accumulation of the tau protein in neurons, neurodegeneration and memory loss. However, the role of non-neuronal cells in this chain of events remains unclear. In the present study, we found accumulation of tau in hilar astrocytes of the dentate gyrus of individuals with AD. In mice, the overexpression of 3R tau specifically in hilar astrocytes of the dentate gyrus altered mitochondrial dynamics and function. In turn, these changes led to a reduction of adult neurogenesis, parvalbumin-expressing neurons, inhibitory synapses and hilar gamma oscillations, which were accompanied by impaired spatial memory performances. Together, these results indicate that the loss of tau homeostasis in hilar astrocytes of the dentate gyrus is sufficient to induce AD-like symptoms, through the impairment of the neuronal network. These results are important for our understanding of disease mechanisms and underline the crucial role of astrocytes in hippocampal function.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Astrocitos/metabolismo , Giro Dentado/metabolismo , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/psicología , Proteínas tau/metabolismo , Enfermedad de Alzheimer/complicaciones , Animales , Animales Modificados Genéticamente , Femenino , Humanos , Trastornos de la Memoria/etiología , Ratones , Ratones Endogámicos C57BL , Red Nerviosa/metabolismo , Neurogénesis , Parvalbúminas/metabolismo , Embarazo , Desempeño Psicomotor , Ratas , Memoria Espacial , Sinapsis/fisiologíaRESUMEN
Alzheimer's disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated ß-amyloid peptides (Aß) and tau proteins. Iatrogenic induction of Aß is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with Aß. Induction of Aß and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer's disease brain homogenates, with very limited functional consequences. Unlike rodents, primates naturally express Aß or tau under normal conditions and attempts to transmit Alzheimer pathology to primates have been made for decades. However, none of earlier studies performed any detailed functional assessments. For the first time we demonstrate long term memory and learning impairments in a non-human primate (Microcebus murinus) following intracerebral injections with Alzheimer human brain extracts. Animals inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel-based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aß depositions and tau lesions for some of them, in regions close to the inoculation sites. Although these lesions were sparse, they were never detected in control animals. Tau-positive animals had the lowest performances in a memory task and displayed the greatest neuronal loss. Our study is timely and important as it is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer's disease brain homogenates in a primate. Clinical signs in a chronic disease such as Alzheimer take a long time to be detectable. Documentation of clinical deterioration and/or dysfunction following intracerebral inoculations with Alzheimer human brain extracts could lead to important new insights about Alzheimer initiation processes.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Encefalopatías/diagnóstico por imagen , Encefalopatías/genética , Encéfalo/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Animales , Encéfalo/patología , Encefalopatías/patología , Cheirogaleidae , Electroencefalografía/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Ratones , Ratones Transgénicos , Primates , Especificidad de la EspecieRESUMEN
Tauopathies are neurodegenerative diseases characterized by the intraneuronal accumulation of aggregated tau. The staging of this neurodegenerative process is well established for Alzheimer's disease as well as for other tauopathies. The stereotypical pattern of tau pathology in these diseases is consistent with the hypothesis that the tau protein can spread in a 'prion-like' manner. It proposes that extracellular pathological tau species can transmit pathology from cell to cell. Accordingly, by targeting these spreading species with therapeutic antibodies one should be able to slow or halt the progression of tau pathology. To be effective, antibodies should neutralize the pathological species present in Alzheimer's disease brains and block their cell-to-cell spread. To evaluate both aspects, tau antibody D, which recognizes an epitope in the central region of tau, and was selected for its outstanding ability to block tau seeding in cell based assays, was used in this study. Here, we addressed two fundamental questions: (i) can this anti-tau antibody neutralize the pathological species present in Alzheimer's disease brains; and (ii) can it block the cell-to-cell spread of tau seeds in vivo? First, antibody D effectively prevented the induction of tau pathology in the brains of transgenic mice that had been injected with human Alzheimer's disease brain extracts, showing that it could effectively neutralize the pathological species present in these extracts. Second, by using K18 P301L tau fibrils to induce pathology, we further demonstrated that antibody D was also capable of blocking the progression of tau pathology to distal brain regions. In contrast, an amino-terminal tau antibody, which was less effective at blocking tau seeding in vitro showed less efficacy in reducing Alzheimer's disease patient tau driven pathology in the transgenic mouse model. We did not address whether the same is true for a spectrum of other amino-terminal antibodies that were tested in vitro. These data highlight important differences between tau antibodies and, when taken together with other recently published data, suggest that epitope may be important for function.
Asunto(s)
Enfermedad de Alzheimer/patología , Ovillos Neurofibrilares/patología , Tauopatías/metabolismo , Proteínas tau/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/terapia , Animales , Anticuerpos/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Epítopos , Femenino , Factores Inmunológicos/metabolismo , Inmunoterapia , Masculino , Ratones Transgénicos , Proteínas tau/metabolismoRESUMEN
Alzheimer's Disease is a devastating dementing disease involving amyloid deposits, neurofibrillary tangles, progressive and irreversible cognitive impairment. Today, only symptomatic drugs are available and therapeutic treatments, possibly acting at a multiscale level, are thus urgently needed. To that purpose, we designed multi-effects compounds by synthesizing drug candidates derived by substituting a novel N,N'-disubstituted piperazine anti-amyloid scaffold and adding acetylcholinesterase inhibition property. Two compounds were synthesized and evaluated. The most promising hybrid molecule reduces both the amyloid pathology and the Tau pathology as well as the memory impairments in a preclinical model of Alzheimer's disease. In vitro also, the compound reduces the phosphorylation of Tau and inhibits the release of Aß peptides while preserving the processing of other metabolites of the amyloid precursor protein. We synthetized and tested the first drug capable of ameliorating both the amyloid and Tau pathology in animal models of AD as well as preventing the major brain lesions and associated memory impairments. This work paves the way for future compound medicines against both Alzheimer's-related brain lesions development and the associated cognitive impairments.
Asunto(s)
Enfermedad de Alzheimer/patología , Encéfalo/efectos de los fármacos , Degeneración Nerviosa/patología , Fármacos Neuroprotectores/farmacología , Piperazinas/farmacología , Animales , Línea Celular , Modelos Animales de Enfermedad , Humanos , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/efectos de los fármacos , Placa Amiloide/patologíaRESUMEN
Accumulation of hyper-phosphorylated and aggregated Tau proteins is a neuropathological hallmark of Alzheimer's Disease (AD) and Tauopathies. AD patient brains also exhibit insulin resistance. Whereas, under normal physiological conditions insulin signaling in the brain mediates plasticity and memory formation, it can also regulate peripheral energy homeostasis. Thus, in AD, brain insulin resistance affects both cognitive and metabolic changes described in these patients. While a role of Aß oligomers and APOE4 towards the development of brain insulin resistance emerged, contribution of Tau pathology has been largely overlooked. Our recent data demonstrated that one of the physiological function of Tau is to sustain brain insulin signaling. We postulated that under pathological conditions, hyper-phosphorylated/aggregated Tau is likely to lose this function and to favor the development of brain insulin resistance. This hypothesis was substantiated by observations from patient brains with pure Tauopathies. To address the potential link between Tau pathology and brain insulin resistance, we have evaluated the brain response to insulin in a transgenic mouse model of AD-like Tau pathology (THY-Tau22). Using electrophysiological and biochemical evaluations, we surprisingly observed that, at a time when Tau pathology and cognitive deficits are overt and obvious, the hippocampus of THY-Tau22 mice exhibits enhanced response to insulin. In addition, we demonstrated that the ability of i.c.v. insulin to promote body weight loss is enhanced in THY-Tau22 mice. In line with this, THY-Tau22 mice exhibited a lower body weight gain, hypoleptinemia and hypoinsulinemia and finally a metabolic resistance to high-fat diet. The present data highlight that the brain of transgenic Tau mice exhibit enhanced brain response to insulin. Whether these observations are ascribed to the development of Tau pathology, and therefore relevant to human Tauopathies, or unexpectedly results from the Tau transgene overexpression is debatable and discussed.
Asunto(s)
Encéfalo/metabolismo , Insulina/metabolismo , Tauopatías/metabolismo , Proteínas tau/metabolismo , Animales , Resistencia a la Insulina/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas tau/genéticaRESUMEN
Tauopathies are a heterogeneous group of pathologies characterized by tau aggregation inside neurons. Most of them are sporadic but certain tauopathies rely on tau gene (MAPT) mutations. They particularly differ from one to another by their different neuropathological signatures e.g. lesion shapes, regions affected and molecular composition of aggregates. Six isoforms of tau exist, but they do not all co-aggregate in each tauopathy but rather have a unique signature for each one. In some tauopathies such as Alzheimer's disease (AD), tau protein aggregation follows stereotypical anatomical stages. Recent data suggest that this progression is due to an active process of tau protein propagation from neuron-to-neuron. We wondered how tau isoforms or mutations could influence the process of tau aggregation and tau propagation. In human neuropathological material, we found that MAPT mutations induce a faster misfolding compared to tau found in sporadic AD patients. In the rat brain, we observed cell-to-cell transfer of non-pathological tau species irrespective of the tested isoform or presence of a mutation. By contrast, we found that the species of tau impact the propagation of tau pathology markers such as hyperphosphorylation and misfolding. Indeed, misfolding and hyperphosphorylated tau proteins do not spread at the same rate when tau is mutated, or the isoform composition is modified. These results clearly argue for the existence of specific folding properties of tau depending on isoforms or mutations impacting the behavior of pathological tau species.
Asunto(s)
Deficiencias en la Proteostasis/complicaciones , Tauopatías , Proteínas tau/genética , Proteínas tau/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Inyecciones Intraventriculares , Masculino , Persona de Mediana Edad , Mutación/genética , Fosforilación , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratas , Ratas Wistar , Índice de Severidad de la Enfermedad , Tauopatías/etiología , Tauopatías/genética , Tauopatías/metabolismo , Tauopatías/patologíaRESUMEN
Tauopathies, such as Alzheimer's disease, are characterized by intracellular aggregates of insoluble Tau proteins. Originally described as a microtubule binding protein, recent studies demonstrated additional physiological roles for Tau. The fact that a single protein can regulate multiple cellular functions has posed challenge in terms of understanding mechanistic cues behind the pathology. Here, we used tandem-affinity purification methodology coupled to mass spectrometry to identify novel interaction partners. We found that Tau interacts with DDX6, a DEAD box RNA helicase involved in translation repression and mRNA decay as well as in the miRNA pathway. Our results demonstrate that Tau increases the silencing activity of the miRNA let-7a, miR-21 and miR-124 through DDX6. Importantly, Tau mutations (P301S, P301L) found in the inherited tauopathies, frontotemporal dementia and parkinsonism linked to chromosome 17, disrupt Tau/DDX6 interaction and impair gene silencing by let-7a. Altogether, these data demonstrated a new unexpected role for Tau in regulating miRNA activity.
Asunto(s)
ARN Helicasas DEAD-box/metabolismo , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas tau/metabolismo , Encéfalo/metabolismo , Línea Celular Tumoral , ARN Helicasas DEAD-box/química , Humanos , Mutación , Dominios y Motivos de Interacción de Proteínas , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas c-myc/metabolismo , Tauopatías/metabolismo , Proteínas tau/química , Proteínas tau/genéticaRESUMEN
Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) and mitigates both amyloid and Tau lesions in transgenic mouse models of the disease. While short-term treatment with A2AR antagonists have been shown to alleviate cognitive deficits in mouse models of amyloidogenesis, impact of a chronic and long-term treatment on the development of amyloid burden, associated neuroinflammation and memory deficits has never been assessed. In the present study, we have evaluated the effect of a 6-month treatment of APPsw/PS1dE9 mice with the potent and selective A2AR antagonist MSX-3 from 3 to 9-10 months of age. At completion of the treatment, we found that the MSX-3 treatment prevented the development of memory deficits in APP/PS1dE9 mice, without significantly altering hippocampal and cortical gene expressions. Interestingly, MSX-3 treatment led to a significant decrease of Aß1-42 levels in the cortex of APP/PS1dE9 animals, while Aß1-40 increased, thereby strongly affecting the Aß1-42/Aß1-40 ratio. Together, these data support the idea that A2AR blockade is of therapeutic value for AD.
RESUMEN
Alzheimer's disease is characterized by the combined presence of amyloid plaques and tau pathology, the latter being correlated with the progression of clinical symptoms. Neuroinflammatory changes are thought to be major contributors to Alzheimer's disease pathophysiology, even if their precise role still remains largely debated. Notably, to what extent immune responses contribute to cognitive impairments promoted by tau pathology remains poorly understood. To address this question, we took advantage of the THY-Tau22 mouse model that progressively develops hippocampal tau pathology paralleling cognitive deficits and reappraised the interrelationship between tau pathology and brain immune responses. In addition to conventional astroglial and microglial responses, we identified a CD8-positive T cell infiltration in the hippocampus of tau transgenic mice associated with an early chemokine response, notably involving CCL3. Interestingly, CD8-positive lymphocyte infiltration was also observed in the cortex of patients exhibiting frontemporal dementia with P301L tau mutation. To gain insights into the functional involvement of T cell infiltration in the pathophysiological development of tauopathy in THY-Tau22 mice, we chronically depleted T cells using anti-CD3 antibody. Such anti-CD3 treatment prevented hippocampal T cell infiltration in tau transgenic animals and reverted spatial memory deficits, in absence of tau pathology modulation. Altogether, these data support an instrumental role of hippocampal T cell infiltration in tau-driven pathophysiology and cognitive impairments in Alzheimer's disease and other tauopathies.
Asunto(s)
Anticuerpos/uso terapéutico , Complejo CD3/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Corteza Cerebral/inmunología , Quimiocinas/inmunología , Disfunción Cognitiva/inmunología , Hipocampo/inmunología , Inflamación/inmunología , Tauopatías/inmunología , Anciano , Animales , Disfunción Cognitiva/terapia , Modelos Animales de Enfermedad , Humanos , Inflamación/terapia , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Tauopatías/terapiaRESUMEN
Chemokines are signaling molecules playing an important role in immune regulations. They are also thought to regulate brain development, neurogenesis and neuroendocrine functions. While chemokine upsurge has been associated with conditions characterized with cognitive impairments, their ability to modulate synaptic plasticity remains ill-defined. In the present study, we specifically evaluated the effects of MIP1-α/CCL3 towards hippocampal synaptic transmission, plasticity and spatial memory. We found that CCL3 (50 ng/ml) significantly reduced basal synaptic transmission at the Schaffer collateral-CA1 synapse without affecting NMDAR-mediated field potentials. This effect was ascribed to post-synaptic regulations, as CCL3 did not impact paired-pulse facilitation. While CCL3 did not modulate long-term depression (LTD), it significantly impaired long-term potentiation (LTP), an effect abolished by Maraviroc, a CCR5 specific antagonist. In addition, sub-chronic intracerebroventricular (icv) injections of CCL3 also impair LTP. In accordance with these electrophysiological findings, we demonstrated that the icv injection of CCL3 in mouse significantly impaired spatial memory abilities and long-term memory measured using the two-step Y-maze and passive avoidance tasks. These effects of CCL3 on memory were inhibited by Maraviroc. Altogether, these data suggest that the chemokine CCL3 is an hippocampal neuromodulator able to regulate synaptic plasticity mechanisms involved in learning and memory functions.
Asunto(s)
Quimiocina CCL3/farmacología , Hipocampo/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Memoria/efectos de los fármacos , Neurotransmisores/farmacología , Transmisión Sináptica/efectos de los fármacos , Animales , Quimiocina CCL3/metabolismo , Masculino , Ratones , Neurotransmisores/metabolismoRESUMEN
Alzheimer's disease (AD) is characterized by both amyloid and Tau pathologies. The amyloid component and altered cholesterol metabolism are closely linked, but the relationship between Tau pathology and cholesterol is currently unclear. Brain cholesterol is synthesized in situ and cannot cross the blood-brain barrier: to be exported from the central nervous system into the blood circuit, excess cholesterol must be converted to 24S-hydroxycholesterol by the cholesterol 24-hydroxylase encoded by the CYP46A1 gene. In AD patients, the concentration of 24S-hydroxycholesterol in the plasma and the cerebrospinal fluid are lower than in healthy controls. The THY-Tau22 mouse is a model of AD-like Tau pathology without amyloid pathology. We used this model to investigate the potential association between Tau pathology and CYP46A1 modulation. The amounts of CYP46A1 and 24S-hydroxycholesterol in the hippocampus were lower in THY-Tau22 than control mice. We used an adeno-associated virus (AAV) gene transfer strategy to increase CYP46A1 expression in order to investigate the consequences on THY-Tau22 mouse phenotype. Injection of the AAV-CYP46A1 vector into the hippocampus of THY-Tau22 mice led to CYP46A1 and 24S-hydroxycholesterol content normalization. The cognitive deficits, impaired long-term depression and spine defects that characterize the THY-Tau22 model were completely rescued, whereas Tau hyperphosphorylation and associated gliosis were unaffected. These results argue for a causal link between CYP46A1 protein content and memory impairments that result from Tau pathology. Therefore, CYP46A1 may be a relevant therapeutic target for Tauopathies and especially for AD.
Asunto(s)
Trastornos de la Memoria/enzimología , Esteroide Hidroxilasas/metabolismo , Tauopatías/metabolismo , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Colesterol 24-Hidroxilasa , Modelos Animales de Enfermedad , Gliosis/metabolismo , Hipocampo/enzimología , Humanos , Hidroxicolesteroles/metabolismo , Trastornos de la Memoria/genética , Ratones , Ratones Transgénicos , Fosforilación , Esteroide Hidroxilasas/genética , Tauopatías/genética , Proteínas tauRESUMEN
A link between Tau phosphorylation and aggregation has been shown in different models for Alzheimer disease, including yeast. We used human Tau purified from yeast models to generate new monoclonal antibodies, of which three were further characterized. The first antibody, ADx201, binds the Tau proline-rich region independently of the phosphorylation status, whereas the second, ADx215, detects an epitope formed by the Tau N terminus when Tau is not phosphorylated at Tyr(18). For the third antibody, ADx210, the binding site could not be determined because its epitope is probably conformational. All three antibodies stained tangle-like structures in different brain sections of THY-Tau22 transgenic mice and Alzheimer patients, and ADx201 and ADx210 also detected neuritic plaques in the cortex of the patient brains. In hippocampal homogenates from THY-Tau22 mice and cortex homogenates obtained from Alzheimer patients, ADx215 consistently stained specific low order Tau oligomers in diseased brain, which in size correspond to Tau dimers. ADx201 and ADx210 additionally reacted to higher order Tau oligomers and presumed prefibrillar structures in the patient samples. Our data further suggest that formation of the low order Tau oligomers marks an early disease stage that is initiated by Tau phosphorylation at N-terminal sites. Formation of higher order oligomers appears to require additional phosphorylation in the C terminus of Tau. When used to assess Tau levels in human cerebrospinal fluid, the antibodies permitted us to discriminate patients with Alzheimer disease or other dementia like vascular dementia, indicative that these antibodies hold promising diagnostic potential.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Anticuerpos Monoclonales , Encéfalo/patología , Hipocampo/patología , Proteínas tau/química , Proteínas tau/inmunología , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/inmunología , Animales , Biotinilación , Western Blotting , Encéfalo/inmunología , Encéfalo/metabolismo , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Mapeo Epitopo , Hipocampo/inmunología , Hipocampo/metabolismo , Humanos , Inmunización , Técnicas para Inmunoenzimas , Inmunoprecipitación , Espectroscopía de Resonancia Magnética , Microdominios de Membrana , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Ovillos Neurofibrilares , Fragmentos de Péptidos/metabolismo , Fosforilación , Placa Amiloide , Saccharomyces cerevisiae , Proteínas tau/líquido cefalorraquídeoRESUMEN
Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested that Tau may be secreted and play a role in neural network signalling. However, once deregulated, secreted Tau may also participate in the spreading of Tau pathology in hierarchical pathways of neurodegeneration. The mechanisms underlying neuron-to-neuron Tau transfer are still unknown; given the known role of extra-cellular vesicles in cell-to-cell communication, we wondered whether these vesicles could carry secreted Tau. We found, among vesicles, that Tau is predominately secreted in ectosomes, which are plasma membrane-originating vesicles, and when it accumulates, the exosomal pathway is activated.