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1.
Nature ; 590(7844): 122-128, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33473210

RESUMEN

Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1-3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease4-6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions.


Asunto(s)
Envejecimiento/metabolismo , Disfunción Cognitiva/prevención & control , Células Mieloides/metabolismo , Adulto , Anciano , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Animales , Respiración de la Célula , Células Cultivadas , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/genética , Dinoprostona/metabolismo , Metabolismo Energético , Glucosa/metabolismo , Glucógeno/biosíntesis , Glucógeno/metabolismo , Humanos , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Trastornos de la Memoria/tratamiento farmacológico , Ratones , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/metabolismo , Mitocondrias/metabolismo , Células Mieloides/inmunología , Subtipo EP2 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP2 de Receptores de Prostaglandina E/deficiencia , Subtipo EP2 de Receptores de Prostaglandina E/genética , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Transducción de Señal/efectos de los fármacos , Memoria Espacial/efectos de los fármacos
2.
Alzheimers Dement ; 20(7): 4434-4460, 2024 07.
Artículo en Inglés | MEDLINE | ID: mdl-38779814

RESUMEN

INTRODUCTION: Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid beta (Aß) toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)-related degenerative signaling, memory loss, and synaptic dysfunction. METHODS: PTX-BD10-2 (BD10-2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish-APP mutant mice (APPL/S) and wild-type controls. Effects on memory and hippocampal long-term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA sequencing. RESULTS: In APPL/S mice, BD10-2 treatment improved memory and LTP deficits. This was accompanied by normalized phosphorylation of protein kinase B (Akt), calcium-calmodulin-dependent kinase II (CaMKII), and AMPA-type glutamate receptors containing the subunit GluA1; enhanced activity-dependent recruitment of synaptic proteins; and increased excitatory synapse number. BD10-2 also had potentially favorable effects on LTP-dependent complement pathway and synaptic gene transcription. DISCUSSION: BD10-2 prevented APPL/S/Aß-associated memory and LTP deficits, reduced abnormalities in synapse-related signaling and activity-dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response. HIGHLIGHTS: Small molecule modulation of tropomyosin related kinase B (TrkB) and C (TrkC) restores long-term potentiation (LTP) and behavior in an Alzheimer's disease (AD) model. Modulation of TrkB and TrkC regulates synaptic activity-dependent transcription. TrkB and TrkC receptors are candidate targets for translational therapeutics. Electrophysiology combined with transcriptomics elucidates synaptic restoration. LTP identifies neuron and microglia AD-relevant human-mouse co-expression modules.


Asunto(s)
Enfermedad de Alzheimer , Microglía , Receptor trkB , Sinapsis , Animales , Masculino , Ratones , Enfermedad de Alzheimer/tratamiento farmacológico , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Ratones Transgénicos , Microglía/efectos de los fármacos , Microglía/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Receptor trkB/metabolismo , Receptor trkC/metabolismo , Receptor trkC/genética , Sinapsis/efectos de los fármacos , Transcriptoma/efectos de los fármacos
3.
Alzheimers Dement ; 12(9): 964-976, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27107518

RESUMEN

INTRODUCTION: In Alzheimer's disease (AD), pathologic amyloid-beta (Aß) is synaptotoxic and impairs neuronal function at the microscale, influencing brain networks at the macroscale before Aß deposition. The latter can be detected noninvasively, in vivo, using resting-state functional MRI (rsfMRI), a technique used to assess brain functional connectivity (FC). METHODS: RsfMRI was performed longitudinally in TG2576 and PDAPP mice, starting before Aß deposition to determine the earliest FC changes. Additionally, the role of pathologic Aß on early FC alterations was investigated by treating TG2576 mice with the 3D6 anti-Aß-antibody. RESULTS: Both transgenic models showed hypersynchronized FC before Aß deposition and hyposynchronized FC at later stages. Early anti-Aß treatment in TG2576 mice prevented hypersynchronous FC and the associated synaptic impairments and excitatory/inhibitory disbalances. DISCUSSION: Hypersynchrony of FC may be used as a new noninvasive read out of early AD and can be recovered by anti-Aß treatment, encouraging preventive treatment strategies in familial AD.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Enfermedad de Alzheimer/diagnóstico por imagen , Animales , Autoanticuerpos/farmacología , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Circulación Cerebrovascular/fisiología , Sincronización Cortical/fisiología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Estudios Longitudinales , Imagen por Resonancia Magnética , Ratones Transgénicos , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/fisiopatología , Fármacos Neuroprotectores/farmacología , Oxígeno/sangre , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/fisiopatología , Placa Amiloide/prevención & control , Síntomas Prodrómicos , Descanso
4.
Science ; 385(6711): eabm6131, 2024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39172838

RESUMEN

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer's disease (AD), with recent proteomic studies highlighting disrupted glial metabolism in AD. We report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN), rescues hippocampal memory function in mouse preclinical models of AD by restoring astrocyte metabolism. Activation of astrocytic IDO1 by amyloid ß and tau oligomers increases KYN and suppresses glycolysis in an aryl hydrocarbon receptor-dependent manner. In amyloid and tau models, IDO1 inhibition improves hippocampal glucose metabolism and rescues hippocampal long-term potentiation in a monocarboxylate transporter-dependent manner. In astrocytic and neuronal cocultures from AD subjects, IDO1 inhibition improved astrocytic production of lactate and uptake by neurons. Thus, IDO1 inhibitors presently developed for cancer might be repurposed for treatment of AD.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Astrocitos , Glucosa , Glucólisis , Hipocampo , Indolamina-Pirrol 2,3,-Dioxigenasa , Quinurenina , Neuronas , Animales , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Astrocitos/metabolismo , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Hipocampo/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quinurenina/metabolismo , Ácido Láctico/metabolismo , Potenciación a Largo Plazo , Memoria/efectos de los fármacos , Transportadores de Ácidos Monocarboxílicos/metabolismo , Neuronas/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Proteínas tau/metabolismo , Triptófano/metabolismo
5.
bioRxiv ; 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38979192

RESUMEN

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer Disease (AD), and recent proteomic studies highlight a disruption of glial carbohydrate metabolism with disease progression. Here, we report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN) in the first step of the kynurenine pathway, rescues hippocampal memory function and plasticity in preclinical models of amyloid and tau pathology by restoring astrocytic metabolic support of neurons. Activation of IDO1 in astrocytes by amyloid-beta 42 and tau oligomers, two major pathological effectors in AD, increases KYN and suppresses glycolysis in an AhR-dependent manner. Conversely, pharmacological IDO1 inhibition restores glycolysis and lactate production. In amyloid-producing APP Swe -PS1 ΔE9 and 5XFAD mice and in tau-producing P301S mice, IDO1 inhibition restores spatial memory and improves hippocampal glucose metabolism by metabolomic and MALDI-MS analyses. IDO1 blockade also rescues hippocampal long-term potentiation (LTP) in a monocarboxylate transporter (MCT)-dependent manner, suggesting that IDO1 activity disrupts astrocytic metabolic support of neurons. Indeed, in vitro mass-labeling of human astrocytes demonstrates that IDO1 regulates astrocyte generation of lactate that is then taken up by human neurons. In co-cultures of astrocytes and neurons derived from AD subjects, deficient astrocyte lactate transfer to neurons was corrected by IDO1 inhibition, resulting in improved neuronal glucose metabolism. Thus, IDO1 activity disrupts astrocytic metabolic support of neurons across both amyloid and tau pathologies and in a model of AD iPSC-derived neurons. These findings also suggest that IDO1 inhibitors developed for adjunctive therapy in cancer could be repurposed for treatment of amyloid- and tau-mediated neurodegenerative diseases.

6.
bioRxiv ; 2023 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-37781573

RESUMEN

Introduction: TrkB and TrkC receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid-ß (Aß)-toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)-related degenerative signaling, memory loss, and synaptic dysfunction. Methods: PTX-BD10-2 (BD10-2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish-APP mutant mice (APP L/S ) and wild-type controls (WT). Effects on memory and hippocampal long-term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA-sequencing. Results: Memory and LTP deficits in APP L/S mice were attenuated by treatment with BD10-2. BD10-2 prevented aberrant AKT, CaMKII, and GLUA1 phosphorylation, and enhanced activity-dependent recruitment of synaptic proteins. BD10-2 also had potentially favorable effects on LTP-dependent complement pathway and synaptic gene transcription. Conclusions: BD10-2 prevented APP L/S /Aß-associated memory and LTP deficits, reduced abnormalities in synapse-related signaling and activity-dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response.

7.
Alzheimers Res Ther ; 12(1): 100, 2020 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-32838792

RESUMEN

BACKGROUND: Intensive basic and preclinical research into Alzheimer's disease (AD) has yielded important new findings, but they could not yet been translated into effective therapies. One of the reasons is the lack of animal models that sufficiently reproduce the complexity of human AD and the response of human brain circuits to novel treatment approaches. As a step in overcoming these limitations, new App knock-in models have been developed that avoid transgenic APP overexpression and its associated side effects. These mice are proposed to serve as valuable models to examine Aß-related pathology in "preclinical AD." METHODS: Since AD as the most common form of dementia progresses into synaptic failure as a major cause of cognitive deficits, the detailed characterization of synaptic dysfunction in these new models is essential. Here, we addressed this by extracellular and whole-cell patch-clamp recordings in AppNL-G-F mice compared to AppNL animals which served as controls. RESULTS: We found a beginning synaptic impairment (LTP deficit) at 3-4 months in the prefrontal cortex of AppNL-G-F mice that is further aggravated and extended to the hippocampus at 6-8 months. Measurements of miniature EPSCs and IPSCs point to a marked increase in excitatory and inhibitory presynaptic activity, the latter accompanied by a moderate increase in postsynaptic inhibitory function. CONCLUSIONS: Our data reveal a marked impairment of primarily postsynaptic processes at the level of synaptic plasticity but the dominance of a presumably compensatory presynaptic upregulation at the level of elementary miniature synaptic function.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Precursor de Proteína beta-Amiloide/genética , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
8.
Behav Brain Res ; 364: 431-441, 2019 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-29158112

RESUMEN

Amyloid-ß (Aß) peptides occur in the brains of patients with Alzheimer's disease (AD), but their role in functional impairment is still debated. High levels of APP and APP fragments in mice that overexpress APP might confound their use in preclinical research. We examined the occurrence of behavioral, cognitive and neuroimaging changes in APPNL-G-F knock-in mice that display Aß42 amyloidosis in the absence of APP overexpression. Female APPNL-G-F mice (carrying Swedish, Iberian and Arctic APP mutations) were compared to APPNL mice (APP Swedish) at 3, 7 and 10 months. Mice were subjected to a test battery that referred to clinical AD symptoms, comprising cage activity, open field, elevated plus maze, social preference and novelty test, and spatial learning, reversal learning and spatial reference memory performance. Our assessment confirmed that behavior at these early ages was largely unaffected in these mice in accordance with previous reports, with some subtle behavioral changes, mainly in social and anxiety-related test performance. Resting-state functional MRI (rsfMRI) assessed connectivity between hippocampal and prefrontal regions with an established role in flexibility, learning and memory. Increased prefrontal-hippocampal network synchronicity was found in 3-month-old APPNL-G-F mice. These functional changes occurred before prominent amyloid plaque deposition.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Péptidos beta-Amiloides/fisiología , Precursor de Proteína beta-Amiloide/fisiología , Animales , Ansiedad/fisiopatología , Conducta Animal/fisiología , Encéfalo/metabolismo , Cognición/fisiología , Disfunción Cognitiva/fisiopatología , Modelos Animales de Enfermedad , Femenino , Técnicas de Sustitución del Gen , Hipocampo/metabolismo , Imagen por Resonancia Magnética/métodos , Ratones , Ratones Transgénicos , Placa Amiloide/metabolismo , Descanso , Memoria Espacial/fisiología
9.
Sci Rep ; 8(1): 6264, 2018 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-29674739

RESUMEN

Amyloid pathology occurs early in Alzheimer's disease (AD), and has therefore been the focus of numerous studies. Transgenic mouse models have been instrumental to study amyloidosis, but observations might have been confounded by APP-overexpression artifacts. The current study investigated early functional defects in an APP knock-in mouse model, which allows assessing the effects of pathological amyloid-beta (Aß) without interference of APP-artifacts. Female APPNL/NL knock-in mice of 3 and 7 months old were compared to age-matched APPNL-F/NL-F mice with increased Aß42/40 ratio and initial Aß-plaque deposition around 6 months of age. Spatial learning was examined using a Morris water maze protocol consisting of acquisition and reversal trials interleaved with reference memory tests. Functional connectivity (FC) of brain networks was assessed using resting-state functional MRI (rsfMRI). The Morris water maze data revealed that 3 months old APPNL-F/NL-F mice were unable to reach the same reference memory proficiency as APPNL/NL mice after reversal training. This cognitive defect in 3-month-old APPNL-F/NL-F mice coincided with hypersynchronous FC of the hippocampal, cingulate, caudate-putamen, and default-mode-like networks. The occurrence of these defects in APPNL-F/NL-F mice demonstrates that cognitive flexibility and synchronicity of telencephalic activity are specifically altered by early Aß pathology without changes in APP neurochemistry.


Asunto(s)
Red Nerviosa/fisiopatología , Aprendizaje Inverso/fisiología , Aprendizaje Espacial/fisiología , Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Animales , Disfunción Cognitiva/fisiopatología , Técnicas de Sustitución del Gen , Imagen por Resonancia Magnética/métodos , Memoria , Ratones , Ratones Transgénicos , Red Nerviosa/diagnóstico por imagen , Placa Amiloide , Telencéfalo/fisiología
10.
Front Cell Neurosci ; 10: 252, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27872582

RESUMEN

Depotentiation (DP) is a mechanism by which synapses that have recently undergone long-term potentiation (LTP) can reverse their synaptic strengthening within a short time-window after LTP induction. Group 1 metabotropic glutamate receptors (mGluRs) were shown to be involved in different forms of LTP and long-term depression (LTD), but little is known about their roles in DP. Here, we generated DP by applying low-frequency stimulation (LFS) at 5 Hz after LTP had been induced by a single train of theta-burst-stimulation (TBS). While application of LFS for 2 min (DP2') generated only a short-lasting DP that was independent of the activation of N-methyl-D-aspartate receptors (NMDARs) and group 1 mGluRs, LFS given for 8 min (DP8') induced a robust DP that was maintained for at least 2 h. This strong form of DP was contingent on NMDAR activation. Interestingly, DP8' appears to include a metabotropic NMDAR function because it was blocked by the competitive NMDAR antagonist D-AP5 but not by the use-dependent inhibitor MK-801 or high Mg2+. Furthermore, DP8' was enhanced by application of the mGluR1 antagonist (YM 298198, 1 µM). The mGluR5 antagonist 2-Methyl-6(phenylethynyl) pyridine (MPEP, 40 µM), in contrast, failed to affect it. The induction of LTP, in turn, was NMDAR dependent (as tested with D-AP5), and blocked by MPEP but not by YM 298198. These results indicate a functional dissociation of mGluR1 and mGluR5 in two related and consecutively induced types of NMDAR-dependent synaptic plasticity (LTP → DP) with far-reaching consequences for their role in plasticity and learning under normal and pathological conditions.

11.
Sci Rep ; 6: 36489, 2016 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-27819338

RESUMEN

Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA injection into medial prefrontal cortex (mPFC) of C57BL6 mice. In accordance with the NMDAR-mediated synapto- and neurotoxic action of QA, we found an initial increase in excitability and an augmentation of hippocampal long-term potentiation, converting within two weeks into a reduction and impairment, respectively, of these processes. QA-induced mPFC excitotoxicity impaired behavioral flexibility in a reversal variant of the hidden-platform Morris water maze (MWM), whereas regular, extended MWM training was unaffected. QA-induced mPFC damage specifically affected the spatial-cognitive strategies that mice use to locate the platform during reversal learning. These behavioral and cognitive defects coincided with changes in cortical functional connectivity (FC) and hippocampal neuroplasticity. FC between various cortical regions was assessed by resting-state fMRI (rsfMRI) methodology, and mice that had received QA injection into mPFC showed increased FC between various cortical regions. mPFC and hippocampus (HC) are anatomically as well as functionally linked as part of a cortical network that controls higher-order cognitive functions. Together, these observations demonstrate the central functional importance of rodent mPFC as well as the validity of QA-induced mPFC damage as a preclinical rodent model of the early stages of neurodegeneration.


Asunto(s)
Hipocampo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Ácido Quinolínico/farmacología , Aprendizaje Inverso/efectos de los fármacos , Animales , Femenino , Hipocampo/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Imagen por Resonancia Magnética/métodos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
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