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1.
Proc Natl Acad Sci U S A ; 121(34): e2409343121, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39136994

RESUMEN

Mutations in the PSEN genes are the major cause of familial Alzheimer's disease, and presenilin (PS) is the catalytic subunit of γ-secretase, which cleaves type I transmembrane proteins, including the amyloid precursor protein (APP) to release Aß peptides. While PS plays an essential role in the protection of neuronal survival, PSEN mutations also increase the ratio of Aß42/Aß40. Thus, it remains unresolved whether PSEN mutations cause AD via a loss of its essential function or increases of Aß42/Aß40. Here, we test whether the knockin (KI) allele of Psen1 L435F, the most severe FAD mutation located closest to the active site of γ-secretase, causes age-dependent cortical neurodegeneration independent of Aß by crossing various Psen mutant mice to the App-null background. We report that removing Aß completely through APP deficiency has no impact on the age-dependent neurodegeneration in Psen mutant mice, as shown by the absence of effects on the reduced cortical volume and decreases of cortical neurons at the ages of 12 and 18 mo. The L435F KI allele increases Aß42/Aß40 in the cerebral cortex while decreasing de novo production and steady-state levels of Aß42 and Aß40 in the presence of APP. Furthermore, APP deficiency does not alleviate elevated apoptotic cell death in the cerebral cortex of Psen mutant mice at the ages of 2, 12, and 18 mo, nor does it affect the progressive microgliosis in these mice. Our findings demonstrate that Psen1 mutations cause age-dependent neurodegeneration independent of Aß, providing further support for a loss-of-function pathogenic mechanism underlying PSEN mutations.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Corteza Cerebral , Mutación , Presenilina-1 , Presenilina-1/genética , Presenilina-1/metabolismo , Animales , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/genética , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Corteza Cerebral/patología , Corteza Cerebral/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Neuronas/metabolismo , Neuronas/patología , Ratones Transgénicos , Humanos
2.
Proc Natl Acad Sci U S A ; 121(41): e2320034121, 2024 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-39348530

RESUMEN

Diabetic retinopathy (DR) is a common complication of diabetes characterized by vascular pathology and neuroinflammation. Pentraxin 3 (PTX3) is a soluble pattern recognition molecule that functions at the crossroads between innate immunity, inflammation, and tissue remodeling. DR is known to involve inflammatory pathways, although the potential relevance of PTX3 has not been explored. We found that PTX3 protein levels increased in the retina of diabetic mice. Similarly, evaluation of a publicly available transcriptomic human dataset revealed increased PTX3 expression in DR with diabetic macular edema and proliferative retinopathy, when compared to nondiabetic retinas or diabetic retinas without complications. To further understand the role of PTX3 within DR, we employed the streptozotocin-induced diabetes model in PTX3 knockout mice (PTX3KO), which were followed up for 9 mo to evaluate hallmarks of disease progression. In diabetic PTX3KO mice, we observed decreased reactive gliosis, diminished microglia activation, and reduced vasodegeneration, when compared to diabetic PTX3 wild-type littermates. The decrease in DR-associated pathological features in PTX3KO retinas translated into preserved visual function, as evidenced by improved optokinetic response, restored b-wave amplitude in electroretinograms, and attenuated neurodegeneration. We showed that PTX3 induced an inflammatory phenotype in human retinal macroglia, characterized by GFAP upregulation and increased secretion of IL6 and PAI-1. We confirmed that PTX3 was required for TNF-α-induced reactive gliosis, as PTX3KO retinal explants did not up-regulate GFAP in response to TNF-α. This study reveals a unique role for PTX3 as an enhancer of sterile inflammation in DR, which drives pathogenesis and ultimately visual impairment.


Asunto(s)
Proteína C-Reactiva , Diabetes Mellitus Experimental , Retinopatía Diabética , Ratones Noqueados , Retina , Animales , Retinopatía Diabética/metabolismo , Retinopatía Diabética/patología , Retinopatía Diabética/genética , Retinopatía Diabética/fisiopatología , Ratones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Experimental/complicaciones , Retina/metabolismo , Retina/patología , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/genética , Humanos , Componente Amiloide P Sérico/metabolismo , Componente Amiloide P Sérico/genética , Masculino , Ratones Endogámicos C57BL , Inflamación/metabolismo , Inflamación/patología , Microglía/metabolismo , Microglía/patología , Edema Macular/metabolismo , Edema Macular/patología , Edema Macular/genética , Proteínas del Tejido Nervioso
3.
Proc Natl Acad Sci U S A ; 120(42): e2306714120, 2023 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-37816062

RESUMEN

Mutations in the Presenilin (PSEN1 and PSEN2) genes are the major cause of early-onset familial Alzheimer's disease (FAD). Presenilin (PS) is the catalytic subunit of the γ-secretase complex, which cleaves type I transmembrane proteins, such as Notch and the amyloid precursor protein (APP), and plays an evolutionarily conserved role in the protection of neuronal survival during aging. FAD PSEN1 mutations exhibit impaired γ-secretase activity in cell culture, in vitro, and knockin (KI) mouse brains, and the L435F mutation is the most severe in reducing γ-secretase activity and is located closest to the active site of γ-secretase. Here, we report that introduction of the codon-optimized wild-type human PSEN1 cDNA by adeno-associated virus 9 (AAV9) results in broadly distributed, sustained, low to moderate levels of human PS1 (hPS1) expression and rescues impaired γ-secretase activity in the cerebral cortex of Psen mutant mice either lacking PS or expressing the Psen1 L435F KI allele, as evaluated by endogenous γ-secretase substrates of APP and recombinant γ-secretase products of Notch intracellular domain and Aß peptides. Furthermore, introduction of hPS1 by AAV9 alleviates impairments of synaptic plasticity and learning and memory in Psen mutant mice. Importantly, AAV9 delivery of hPS1 ameliorates neurodegeneration in the cerebral cortex of aged Psen mutant mice, as shown by the reversal of age-dependent loss of cortical neurons and elevated microgliosis and astrogliosis. These results together show that moderate hPS1 expression by AAV9 is sufficient to rescue impaired γ-secretase activity, synaptic and memory deficits, and neurodegeneration caused by Psen mutations in mouse models.


Asunto(s)
Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Humanos , Ratones , Animales , Anciano , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Presenilina-1/genética , Presenilina-1/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Mutación , Trastornos de la Memoria/genética , Trastornos de la Memoria/terapia , Presenilina-2/genética , Péptidos beta-Amiloides/metabolismo
4.
Cell Mol Life Sci ; 81(1): 51, 2024 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-38252153

RESUMEN

Retinitis pigmentosa (RP) and macular dystrophy (MD) cause severe retinal dysfunction, affecting 1 in 4000 people worldwide. This disease is currently assumed to be intractable, because effective therapeutic methods have not been established, regardless of genetic or sporadic traits. Here, we examined a RP mouse model in which the Prominin-1 (Prom1) gene was deficient and investigated the molecular events occurring at the outset of retinal dysfunction. We extracted the Prom1-deficient retina subjected to light exposure for a short time, conducted single-cell expression profiling, and compared the gene expression with and without stimuli. We identified the cells and genes whose expression levels change directly in response to light stimuli. Among the genes altered by light stimulation, Igf1 was decreased in rod photoreceptor cells and astrocytes under the light-stimulated condition. Consistently, the insulin-like growth factor (IGF) signal was weakened in light-stimulated photoreceptor cells. The recovery of Igf1 expression with the adeno-associated virus (AAV) prevented photoreceptor cell death, and its treatment in combination with the endothelin receptor antagonist led to the blockade of abnormal glial activation and the promotion of glycolysis, thereby resulting in the improvement of retinal functions, as assayed by electroretinography. We additionally demonstrated that the attenuation of mammalian/mechanistic target of rapamycin (mTOR), which mediates IGF signalling, leads to complications in maintaining retinal homeostasis. Together, we propose that combinatorial manipulation of distinct mechanisms is useful for the maintenance of the retinal condition.


Asunto(s)
Degeneración Macular , Enfermedades de la Retina , Retinitis Pigmentosa , Animales , Ratones , Endotelinas , Factor I del Crecimiento Similar a la Insulina/genética , Retina , Células Fotorreceptoras Retinianas Bastones
5.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35197297

RESUMEN

Muller glia (MG) play a central role in reactive gliosis, a stress response associated with rare and common retinal degenerative diseases, including age-related macular degeneration (AMD). The posttranslational modification citrullination​ targeting glial fibrillary acidic protein (GFAP) in MG was initially discovered in a panocular chemical injury model. Here, we report in the paradigms of retinal laser injury, a genetic model of spontaneous retinal degeneration (JR5558 mice) and human wet-AMD tissues that MG citrullination is broadly conserved. After laser injury, GFAP polymers that accumulate in reactive MG are citrullinated in MG endfeet and glial cell processes. The enzyme responsible for citrullination, peptidyl arginine deiminase-4 (PAD4), localizes to endfeet and associates with GFAP polymers. Glial cell-specific PAD4 deficiency attenuates retinal hypercitrullination in injured retinas, indicating PAD4 requirement for MG citrullination. In retinas of 1-mo-old JR5558 mice, hypercitrullinated GFAP and PAD4 accumulate in MG endfeet/cell processes in a lesion-specific manner. Finally, we show that human donor maculae from patients with wet-AMD also feature the canonical endfeet localization of hypercitrullinated GFAP. Thus, we propose that endfeet are a "citrullination bunker" that initiates and sustains citrullination in retinal degeneration.


Asunto(s)
Citrulinación , Gliosis/metabolismo , Neuroglía/metabolismo , Degeneración Retiniana/metabolismo , Animales , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Degeneración Macular Húmeda/metabolismo
6.
Glia ; 72(3): 546-567, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37987116

RESUMEN

Although brain scars in adults have been extensively studied, there is less data available regarding scar formation during the neonatal period, and the involvement of peripheral immune cells in this process remains unexplored in neonates. Using a murine model of neonatal hypoxic-ischemic encephalopathy (HIE) and confocal microscopy, we characterized the scarring process and examined the recruitment of peripheral immune cells to cortical and hippocampal scars for up to 1 year post-insult. Regional differences in scar formation were observed, including the presence of reticular fibrotic networks in the cortex and perivascular fibrosis in the hippocampus. We identified chemokines with chronically elevated levels in both regions and demonstrated, through a parabiosis-based strategy, the recruitment of lymphocytes, neutrophils, and monocyte-derived macrophages to the scars several weeks after the neonatal insult. After 1 year, however, neutrophils and lymphocytes were absent from the scars. Our data indicate that peripheral immune cells are transient components of HIE-induced brain scars, opening up new possibilities for late therapeutic interventions.


Asunto(s)
Cicatriz , Hipoxia-Isquemia Encefálica , Adulto , Animales , Humanos , Ratones , Cicatriz/patología , Encéfalo/patología , Macrófagos , Hipoxia-Isquemia Encefálica/patología
7.
J Neurochem ; 168(9): 2935-2955, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38943350

RESUMEN

Astrocytes provide metabolic support to neurons, maintain ionic and water homeostasis, and uptake and recycle neurotransmitters. After exposure to the prototypical PAMP lipopolysaccharide (LPS), reactive astrocytes increase the expression of pro-inflammatory genes, facilitating neurodegeneration. In this study, we analyzed the expression of homeostatic genes in astrocytes exposed to LPS and identified the epigenetic factors contributing to the suppression of homeostatic genes in reactive astrocytes. Primary astrocytic cultures were acutely exposed to LPS and allowed to recover for 24, 72 h, and 7 days. As expected, LPS exposure induced reactive astrogliosis and increased the expression of pro-inflammatory IL-1B and IL-6. Interestingly, the acute exposure resulted in persistent hypermethylation of astroglial DNA. Similar hypermethylation was observed in highly reactive astrocytes from the traumatic brain injury (TBI) penumbra in vivo. Hypermethylation was accompanied by decreased expression of homeostatic genes including LDHA and Scl16a1 (MCT1) both involved in the lactate shuttle to neurons; glutamine synthase (GS) responsible for glutamate processing; Kcnj10 (Kir4.1) important for K+ homeostasis, and the water channel aquaporin-4 (Aqp4). Furthermore, the master regulator of DNA methylation, MAFG-1, as well as DNA methyl transferases DNMT1 and DNMT3a were overexpressed. The downregulation of homeostatic genes correlated with increased methylation of CpG islands in their promoters, as assessed by methylation-sensitive PCR and increased DNMT3a binding to the GS promoter. Treatment with decitabine, a DNMT inhibitor, prevented the LPS- and the HMGB-1-induced downregulation of homeostatic genes. Decitabine treatment also prevented the neurotoxic effects of these astrocytes in primary cortical cultures. In summary, our findings reveal that the pathological remodeling of reactive astrocytes encompasses not only the pro-inflammatory response but, significantly, also entails a long-term suppression of homeostatic gene expression with methylation of crucial CpG islands within their promoters.


Asunto(s)
Astrocitos , Metilación de ADN , Regulación hacia Abajo , Homeostasis , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/patología , Metilación de ADN/efectos de los fármacos , Animales , Homeostasis/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Células Cultivadas , Lipopolisacáridos/farmacología , Masculino , Ratones , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/genética , Ratas , Ratones Endogámicos C57BL
8.
Neurobiol Dis ; 198: 106554, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38844243

RESUMEN

Huntington's disease (HD) is a neurodegenerative disorder that severely affects the basal ganglia and regions of the cerebral cortex. While astrocytosis and microgliosis both contribute to basal ganglia pathology, the contribution of gliosis and potential factors driving glial activity in the human HD cerebral cortex is less understood. Our study aims to identify nuanced indicators of gliosis in HD which is challenging to identify in the severely degenerated basal ganglia, by investigating the middle temporal gyrus (MTG), a cortical region previously documented to demonstrate milder neuronal loss. Immunohistochemistry was conducted on MTG paraffin-embedded tissue microarrays (TMAs) comprising 29 HD and 35 neurologically normal cases to compare the immunoreactivity patterns of key astrocytic proteins (glial fibrillary acidic protein, GFAP; inwardly rectifying potassium channel 4.1, Kir4.1; glutamate transporter-1, GLT-1; aquaporin-4, AQP4), key microglial proteins (ionised calcium-binding adapter molecule-1, IBA-1; human leukocyte antigen (HLA)-DR; transmembrane protein 119, TMEM119; purinergic receptor P2RY12, P2RY12), and indicators of proliferation (Ki-67; proliferative cell nuclear antigen, PCNA). Our findings demonstrate an upregulation of GFAP+ protein expression attributed to the presence of more GFAP+ expressing cells in HD, which correlated with greater cortical mutant huntingtin (mHTT) deposition. In contrast, Kir4.1, GLT-1, and AQP4 immunoreactivity levels were unchanged in HD. We also demonstrate an increased number of IBA-1+ and TMEM119+ microglia with somal enlargement. IBA-1+, TMEM119+, and P2RY12+ reactive microglia immunophenotypes were also identified in HD, evidenced by the presence of rod-shaped, hypertrophic, and dystrophic microglia. In HD cases, IBA-1+ cells contained either Ki-67 or PCNA, whereas GFAP+ astrocytes were devoid of proliferative nuclei. These findings suggest cortical microgliosis may be driven by proliferation in HD, supporting the hypothesis of microglial proliferation as a feature of HD pathophysiology. In contrast, astrocytes in HD demonstrate an altered GFAP expression profile that is associated with the degree of mHTT deposition.


Asunto(s)
Astrocitos , Proliferación Celular , Enfermedad de Huntington , Microglía , Humanos , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Microglía/metabolismo , Microglía/patología , Astrocitos/metabolismo , Astrocitos/patología , Masculino , Femenino , Persona de Mediana Edad , Proliferación Celular/fisiología , Adulto , Anciano , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Proteínas de Unión al Calcio/metabolismo , Gliosis/metabolismo , Gliosis/patología , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas de la Membrana , Proteínas de Microfilamentos
9.
Neurobiol Dis ; 201: 106671, 2024 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-39293688

RESUMEN

Dipeptidyl peptidase 4 (DPP4; CD26) is involved in the regulation of various metabolic, immunological, and neurobiological processes in healthy individuals. Observations based on epidemiological data indicate that DPP4 inhibition by gliptins, typically used in patients with diabetes, may reduce the risk for cerebral ischemia and may also improve related outcomes. However, as DPP4 inhibitor application is neither complete nor specific for suppression of DPP4 enzymatic activity and DPP4 has non-enzymatic functions as well, the variety of consequences is a matter of debate. Therefore, we here used DPP4 knock-out (KO) mice to analyze the specific contribution of DPP4 to cellular, immunological, and functional consequences of experimental focal cerebral ischemia. We observed a significantly higher survival rate of DPP4 KO mice after ischemia, which was accompanied by a lower abundance of the pro-inflammatory chemokine CCL2 and reduced activation of Iba1-positive microglia cells in brain tissue of DPP4 KO mice. In addition, after ischemia for 24 h to 72 h, decreased concentrations of CCL5 and CCL12 in plasma and of CCL17 in brain tissue of DPP4 KO mice were observed when compared to wild type mice. Other aspects analyzed, such as the functional Menzies score, astrocyte activation and chemokine levels in plasma and brain tissue were affected by ischemia but appeared to be unaffected by the DPP4 KO genotype. Taken together, experimental ablation of DPP4 functions in mice improves survival and ameliorates aspects of cellular and molecular inflammation after focal cerebral ischemia.


Asunto(s)
Isquemia Encefálica , Dipeptidil Peptidasa 4 , Microglía , Animales , Masculino , Ratones , Encéfalo/metabolismo , Encéfalo/patología , Isquemia Encefálica/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Dipeptidil Peptidasa 4/deficiencia , Inflamación/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/metabolismo
10.
Eur J Neurosci ; 59(11): 3009-3029, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38576159

RESUMEN

Metabolic disorders are risk factors for stroke exacerbating subsequent complications. Rapidly after brain injury, a glial scar forms, preventing excessive inflammation and limiting axonal regeneration. Despite the growing interest in wound healing following brain injury, the formation of a glial scar in the context of metabolic disorders is poorly documented. In this study, we used db/db mice to investigate the impact of metabolic perturbations on brain repair mechanisms, with a focus on glial scarring. First, we confirmed the development of obesity, poor glucose regulation, hyperglycaemia and liver steatosis in these mice. Then, we observed that 3 days after a 30-min middle cerebral artery occlusion (MCAO), db/db mice had larger infarct area compared with their control counterparts. We next investigated reactive gliosis and glial scar formation in db/+ and db/db mice. We demonstrated that astrogliosis and microgliosis were exacerbated 3 days after stroke in db/db mice. Furthermore, we also showed that the synthesis of extracellular matrix (ECM) proteins (i.e., chondroitin sulphate proteoglycan, collagen IV and tenascin C) was increased in db/db mice. Consequently, we demonstrated for the first time that metabolic disorders impair reactive gliosis post-stroke and increase ECM deposition. Given that the damage size is known to influence glial scar, this study now raises the question of the direct impact of hyperglycaemia/obesity on reactive gliosis and glia scar. It paves the way to promote the development of new therapies targeting glial scar formation to improve functional recovery after stroke in the context of metabolic disorders.


Asunto(s)
Cicatriz , Gliosis , Infarto de la Arteria Cerebral Media , Animales , Gliosis/metabolismo , Gliosis/patología , Ratones , Cicatriz/metabolismo , Cicatriz/patología , Infarto de la Arteria Cerebral Media/metabolismo , Neuroglía/metabolismo , Neuroglía/patología , Masculino , Ratones Endogámicos C57BL , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/etiología , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Obesidad/metabolismo , Obesidad/complicaciones , Proteínas de la Matriz Extracelular/metabolismo , Hiperglucemia/metabolismo
11.
J Neuroinflammation ; 21(1): 190, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39095775

RESUMEN

Retinitis pigmentosa (RP), an inherited retinal disease, affects 1,5 million people worldwide. The initial mutation-driven photoreceptor degeneration leads to chronic inflammation, characterized by Müller cell activation and upregulation of CD44. CD44 is a cell surface transmembrane glycoprotein and the primary receptor for hyaluronic acid. It is involved in many pathological processes, but little is known about CD44's retinal functions. CD44 expression is also increased in Müller cells from our Pde6bSTOP/STOP RP mouse model. To gain a more detailed understanding of CD44's role in healthy and diseased retinas, we analyzed Cd44-/- and Cd44-/-Pde6bSTOP/STOP mice, respectively. The loss of CD44 led to enhanced photoreceptor degeneration, reduced retinal function, and increased inflammatory response. To understand the underlying mechanism, we performed proteomic analysis on isolated Müller cells from Cd44-/- and Cd44-/-Pde6bSTOP/STOP retinas and identified a significant downregulation of glutamate transporter 1 (SLC1A2). This downregulation was accompanied by higher glutamate levels, suggesting impaired glutamate homeostasis. These novel findings indicate that CD44 stimulates glutamate uptake via SLC1A2 in Müller cells, which in turn, supports photoreceptor survival and function.


Asunto(s)
Células Ependimogliales , Receptores de Hialuranos , Retinitis Pigmentosa , Transducción de Señal , Animales , Receptores de Hialuranos/metabolismo , Receptores de Hialuranos/genética , Ratones , Células Ependimogliales/metabolismo , Transducción de Señal/fisiología , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/patología , Retinitis Pigmentosa/genética , Ratones Noqueados , Ratones Endogámicos C57BL , Células Fotorreceptoras de Vertebrados/metabolismo , Supervivencia Celular/fisiología , Ratones Transgénicos , Retina/metabolismo , Retina/patología
12.
J Neuroinflammation ; 21(1): 200, 2024 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-39129007

RESUMEN

BACKGROUND: We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer's disease (AD). However, the effects of CA140 on Aß/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown. METHODS: To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted. RESULTS: In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aß/tau fibrillation, Aß plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100ß and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling. CONCLUSIONS: Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aß/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ratones Transgénicos , Enfermedades Neuroinflamatorias , Receptores de Dopamina D1 , Transducción de Señal , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Ratones , Péptidos beta-Amiloides/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Receptores de Dopamina D1/metabolismo , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/patología , Cognición/efectos de los fármacos , Dopamina/metabolismo , Ratones Endogámicos C57BL , Masculino , Humanos
13.
J Neuroinflammation ; 21(1): 18, 2024 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-38212822

RESUMEN

Lipoxins are small lipids that are potent endogenous mediators of systemic inflammation resolution in a variety of diseases. We previously reported that Lipoxins A4 and B4 (LXA4 and LXB4) have protective activities against neurodegenerative injury. Yet, lipoxin activities and downstream signaling in neuroinflammatory processes are not well understood. Here, we utilized a model of posterior uveitis induced by lipopolysaccharide endotoxin (LPS), which results in rapid retinal neuroinflammation primarily characterized by activation of resident macroglia (astrocytes and Müller glia), and microglia. Using this model, we observed that each lipoxin reduces acute inner retinal inflammation by affecting endogenous glial responses in a cascading sequence beginning with astrocytes and then microglia, depending on the timing of exposure; prophylactic or therapeutic. Subsequent analyses of retinal cytokines and chemokines revealed inhibition of both CXCL9 (MIG) and CXCL10 (IP10) by each lipoxin, compared to controls, following LPS injection. CXCL9 and CXCL10 are common ligands for the CXCR3 chemokine receptor, which is prominently expressed in inner retinal astrocytes and ganglion cells. We found that CXCR3 inhibition reduces LPS-induced neuroinflammation, while CXCR3 agonism alone induces astrocyte reactivity. Together, these data uncover a novel lipoxin-CXCR3 pathway to promote distinct anti-inflammatory and proresolution cascades in endogenous retinal glia.


Asunto(s)
Lipoxinas , Neuroglía , Enfermedades Neuroinflamatorias , Receptores CXCR3 , Inflamación/inducido químicamente , Lipopolisacáridos/toxicidad , Lipoxinas/farmacología , Lipoxinas/metabolismo , Neuroglía/metabolismo , Animales
14.
Acta Neuropathol ; 148(1): 52, 2024 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-39394356

RESUMEN

Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer's disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas Reguladoras de la Apoptosis , Autofagia , Lesiones Traumáticas del Encéfalo , Disfunción Cognitiva , Lisosomas , Neuronas , Proteínas tau , Animales , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/complicaciones , Autofagia/fisiología , Proteínas tau/metabolismo , Humanos , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Fosforilación , Ratones , Neuronas/metabolismo , Neuronas/patología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Lisosomas/metabolismo , Masculino , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Reguladoras de la Apoptosis/genética , Ratones Endogámicos C57BL , Ratones Transgénicos , Sinapsis/patología , Sinapsis/metabolismo , Femenino , Persona de Mediana Edad
15.
Brain Behav Immun ; 123: 681-696, 2024 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-39406266

RESUMEN

Capillary pericytes are important regulators of cerebral blood flow, blood-brain barrier integrity and neuroinflammation, but can become lost or dysfunctional in disease. The consequences of pericyte loss or dysfunction is extremely difficult to discern when it forms one component of a complex disease process. To evaluate this directly, we examined the effect of adult pericyte loss on mouse voluntary movement and motor function, and physiological responses such as hypoxia, blood-brain barrier (BBB) integrity and glial reactivity. Tamoxifen delivery to Pdgfrß-CreERT2:: Rosa26-DTA transgenic mice was titrated to produce a dose-dependent ablation of pericytes in vivo. 100mg/kg of tamoxifen ablated approximately half of all brain pericytes, while two consecutive daily doses of 300mg/kg tamoxifen ablated >80% of brain pericytes. In the open field test, mice with âˆ¼50% pericyte loss spent more time immobile and travelled half the distance of control mice. Mice with >80% pericyte ablation also slipped more frequently while performing the beam walk task. Our histopathological analyses of the brain revealed that blood vessel density was unchanged, but vessel lumen width was increased. Pericyte-ablated mice also exhibited: mild BBB disruption; increased neuronal hypoxia; astrogliosis and increased IBA1+ immunoreactivity, suggestive of microgliosis and/or macrophage infiltration. Our results highlight the importance of pericytes in the brain, as pericyte loss can directly compromise brain health and induce behavioural alterations in mice.

16.
Neurochem Res ; 49(12): 3356-3366, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39302596

RESUMEN

Hypothalamic inflammation underlies diet-induced obesity and diabetes in rodent models. While diet normalization largely allows for recovery from metabolic impairment, it remains unknown whether long-term hypothalamic inflammation induced by obesogenic diets is a reversible process. In this study, we aimed at determining sex specificity of hypothalamic neuroinflammation and gliosis in mice fed a fat- and sugar-rich diet, and their reversibility upon diet normalization. Mice were fed a 60%-fat diet complemented by a 20% sucrose drink (HFHSD) for 3 days or 24 weeks, followed by a third group that had their diet normalized for the last 8 weeks of the study (reverse diet group, RevD). We determined the expression of pro- and anti-inflammatory cytokines, and of the inflammatory cell markers IBA1, CD68, GFAP and EMR1 in the hypothalamus, and analyzed morphology of microglia (IBA-1+ cells) and astrocytes (GFAP+ cells) in the arcuate nucleus. After 3 days of HFHSD feeding, male mice showed over-expression of IL-13, IL-18, IFN-γ, CD68 and EMR1 and reduced expression of IL-10, while females showed increased IL-6 and IBA1 and reduced IL-13, compared to controls. After 24 weeks of HFHSD exposure, male mice showed a general depression in the expression of cytokines, with prominent reduction of TNF-α, IL-6 and IL-13, but increased TGF-ß, while female mice showed over-expression of IFN-γ and IL-18. Furthermore, both female and male mice showed some degree of gliosis after HFHSD feeding for 24 weeks. In mice of both sexes, diet normalization after prolonged HFHSD feeding resulted in partial neuroinflammation recovery in the hypothalamus, but gliosis was only recovered in females. In sum, HFHSD-fed mice display sex-specific inflammatory processes in the hypothalamus that are not fully reversible after diet normalization.


Asunto(s)
Dieta Alta en Grasa , Hipotálamo , Inflamación , Ratones Endogámicos C57BL , Caracteres Sexuales , Animales , Masculino , Femenino , Dieta Alta en Grasa/efectos adversos , Hipotálamo/metabolismo , Hipotálamo/patología , Ratones , Inflamación/metabolismo , Inflamación/patología , Citocinas/metabolismo , Gliosis/patología , Gliosis/metabolismo , Microglía/metabolismo , Sacarosa en la Dieta
17.
Toxicol Pathol ; 52(2-3): 114-122, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38828567

RESUMEN

Gliosis, including microgliosis and astrocytosis, can be challenging to interpret in nonclinical studies. Incidences of glial foci in brains and spinal cords of control rats and nonhuman primates (NHPs) were reviewed in the historical control databases from two contract research organizations, including one specializing in neuropathology. In the brain, minimal to mild (grades 1-2) microgliosis was the most common diagnosis, especially in NHPs, although occasional moderate or marked microgliosis (grades 3 and 4) was encountered in both species. Microgliosis was more common in the cerebral cortex, cerebellum, and medulla oblongata in both species and was frequent in the white matter (brain), thalamus, and basal nuclei of NHPs. Gliosis ("not otherwise specified") of minimal severity was diagnosed in similar brain sub-sites for both species and was more common in NHPs compared with rats. Astrocytosis was most prominent in the cerebellum (molecular layer) of NHPs but was otherwise uncommon. In the spinal cord, microgliosis was most common in the lateral white matter tracts in rats and NHPs, and in the dorsal white matter tracts in NHPs. These data indicate that low-grade spontaneous glial responses occur with some frequency in control animals of two common nonclinical species.


Asunto(s)
Gliosis , Médula Espinal , Animales , Gliosis/patología , Ratas , Médula Espinal/patología , Masculino , Encéfalo/patología , Femenino , Sistema Nervioso Central/patología , Macaca fascicularis
18.
Toxicol Pathol ; 52(5): 295-301, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39149788

RESUMEN

Degenerative lesions specific to the basal nuclei have not been described as a background finding in Beagle dogs. This report comprises a documentation of seven cases. In the context of a nonclinical safety studies, the authors suggest documenting the lesion descriptively as degeneration neuropil, basal nuclei, bilateral as it is characterized by (1) vacuolation, neuropil; (2) gliosis (astro- and/or microgliosis); and (3) demyelination. This novel lesion is considered a potential new background change for several reasons: (1) It occurred in animals from test item-treated and also vehicle-treated groups; (2) no dose dependency was observed; (3) in one of six affected test item-treated dogs, the given compound was shown not to penetrate the blood-brain barrier; and (4) statistical comparison between the proportions of affected dogs in the treatment and control groups did not yield a statistically significant difference. The etiology remains unknown and is subject to further investigations.


Asunto(s)
Encéfalo , Animales , Perros , Masculino , Femenino , Encéfalo/patología , Neurópilo/patología , Gliosis/patología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/veterinaria
19.
Brain ; 146(8): 3416-3430, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-36825472

RESUMEN

Epilepsy, characterized by recurrent unprovoked seizures resulting from a wide variety of causes, is one of the world's most prominent neurological disabilities. Seizures, which are an expression of neuronal network dysfunction, occur in a positive feedback loop of concomitant factors, including neuro-inflammatory responses, where seizures generate more seizures. Among other pathways involved in inflammatory responses, the JAK/STAT signalling pathway has been proposed to participate in epilepsy. Here, we tested an in vitro model of temporal lobe epilepsy, with the hypothesis that acute blockage of STAT3-phosphorylation during epileptogenesis would prevent structural damage in the hippocampal circuitry and the imprinting of both neural epileptic activity and inflammatory glial states. We performed calcium imaging of spontaneous circuit dynamics in organotypic hippocampal slices previously exposed to epileptogenic conditions through the blockage of GABAergic synaptic transmission. Epileptogenic conditions lead to epileptic dynamics imprinted on circuits in terms of increased neuronal firing and circuit synchronization, increased correlated activity in neuronal pairs and decreased complexity in synchronization patterns. Acute blockage of the STAT3-phosphorylation during epileptogenesis prevented the imprinting of epileptic activity patterns, general cell loss, loss of GABAergic neurons and the persistence of reactive glial states. This work provides mechanistic evidence that blocking the STAT3 signalling pathway during epileptogenesis can prevent patho-topological persistent reorganization of neuro-glial circuits.


Asunto(s)
Epilepsia del Lóbulo Temporal , Epilepsia , Humanos , Convulsiones/metabolismo , Epilepsia del Lóbulo Temporal/metabolismo , Hipocampo/metabolismo , Neuronas GABAérgicas/metabolismo , Factor de Transcripción STAT3/metabolismo
20.
Brain ; 146(2): 549-560, 2023 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-35978480

RESUMEN

Drug-resistant mesial-temporal lobe epilepsy is a devastating disease with seizure onset in the hippocampal formation. A fraction of hippocampi samples from epilepsy-surgical procedures reveals a peculiar histological pattern referred to as 'gliosis only' with unresolved pathogenesis and enigmatic sequelae. Here, we hypothesize that 'gliosis only' represents a particular syndrome defined by distinct clinical and molecular characteristics. We curated an in-depth multiparameter integration of systematic clinical, neuropsychological as well as neuropathological analysis from a consecutive cohort of 627 patients, who underwent hippocampectomy for drug-resistant temporal lobe epilepsy. All patients underwent either classic anterior temporal lobectomy or selective amygdalohippocampectomy. On the basis of their neuropathological exam, patients with hippocampus sclerosis and 'gliosis only' were characterized and compared within the whole cohort and within a subset of matched pairs. Integrated transcriptional analysis was performed to address molecular differences between both groups. 'Gliosis only' revealed demographics, clinical and neuropsychological outcome fundamentally different from hippocampus sclerosis. 'Gliosis only' patients had a significantly later seizure onset (16.3 versus 12.2 years, P = 0.005) and worse neuropsychological outcome after surgery compared to patients with hippocampus sclerosis. Epilepsy was less amendable by surgery in 'gliosis only' patients, resulting in a significantly worse rate of seizure freedom after surgery in this subgroup (43% versus 68%, P = 0.0001, odds ratio = 2.8, confidence interval 1.7-4.7). This finding remained significant after multivariate and matched-pairs analysis. The 'gliosis only' group demonstrated pronounced astrogliosis and lack of significant neuronal degeneration in contrast to characteristic segmental neuron loss and fibrillary astrogliosis in hippocampus sclerosis. RNA-sequencing of gliosis only patients deciphered a distinct transcriptional programme that resembles an innate inflammatory response of reactive astrocytes. Our data indicate a new temporal lobe epilepsy syndrome for which we suggest the term 'Innate inflammatory gliosis only'. 'Innate inflammatory gliosis only' is characterized by a diffuse gliosis pattern lacking restricted hippocampal focality and is poorly controllable by surgery. Thus, 'innate inflammatory gliosis only' patients need to be clearly identified by presurgical examination paradigms of pharmacoresistant temporal lobe epilepsy patients; surgical treatment of this subgroup should be considered with great precaution. 'Innate inflammatory gliosis only' requires innovative pharmacotreatment strategies.


Asunto(s)
Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Esclerosis del Hipocampo , Humanos , Epilepsia del Lóbulo Temporal/patología , Gliosis/patología , Esclerosis/patología , Hipocampo/patología , Lóbulo Temporal/patología , Epilepsia Refractaria/complicaciones , Resultado del Tratamiento
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