RESUMEN

Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was elevated in obese mice, and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity, and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify essential roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity.

Asunto(s)

Núcleo Arqueado del Hipotálamo/metabolismo , Peso Corporal/fisiología , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular/genética , Homeostasis/genética , Inmunoglobulinas/genética , Obesidad/metabolismo , Animales , Molécula 1 de Adhesión Celular , Metabolismo Energético/fisiología , Estudio de Asociación del Genoma Completo , Homeostasis/fisiología , Proteínas de la Membrana/metabolismo , Ratones Transgénicos , Neuronas/metabolismo , Obesidad/genética , Proopiomelanocortina/metabolismo

RESUMEN

Sortilin is a sorting receptor that directs target proteins, such as growth factors, signaling receptors, and enzymes, to their destined location in secretory or endocytic compartments of cells. The activity of sortilin is essential for proper function of not only neurons but also non-neuronal cell types, and receptor (dys)function emerges as a major cause of malignancies, including hypercholesterolemia, retinal degeneration, neuronal cell loss in stroke and spinal cord injury, or Alzheimer's disease and other neurodegenerative disorders. In this article, we describe the molecular mechanisms of sortilin action in protein sorting and signaling and how modulation of receptor function may offer novel therapeutic strategies for treatment of common diseases of the cardiovascular and nervous systems.

Asunto(s)

Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/análisis , Animales , Humanos , Transporte de Proteínas , Transducción de Señal

RESUMEN

UNLABELLED: Alzheimer disease (AD) is the most common neurodegenerative disease affecting millions of patients worldwide. According to the amyloid cascade hypothesis, the formation of neurotoxic oligomers composed of amyloid-ß (Aß) peptides is the main mechanism that causes synaptic dysfunction and, eventually, neuronal cell death in this condition. Intriguingly, apolipoprotein E (apoE), the most important genetic risk factor for sporadic AD, emerges as a key factor that contributes to many aspects of the amyloid cascade including the clearance of Aß from brain interstitial fluid and the ability of this peptide to form neurotoxic oligomers. Central to the activity of apoE in the healthy and in the diseased brain are apoE receptors that interact with this protein to mediate its multiple cellular and systemic effects. This review describes the molecular interactions that link apoE and its cellular receptors with neuronal viability and function, and how defects in these pathways in the brain promote neurodegeneration. For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Barrera Hematoencefálica/metabolismo , Colesterol/metabolismo , Humanos

RESUMEN

SORLA/SORL1 is a unique neuronal sorting receptor for the amyloid precursor protein that has been causally implicated in both sporadic and autosomal dominant familial forms of Alzheimer's disease (AD). Brain concentrations of SORLA are inversely correlated with amyloid-ß (Aß) in mouse models and AD patients, suggesting that increasing expression of this receptor could be a therapeutic option for decreasing the amount of amyloidogenic products in affected individuals. We characterize a new mouse model in which SORLA is overexpressed, and show a decrease in Aß concentrations in mouse brain. We trace the underlying molecular mechanism to the ability of this receptor to direct lysosomal targeting of nascent Aß peptides. Aß binds to the amino-terminal VPS10P domain of SORLA, and this binding is impaired by a familial AD mutation in SORL1. Thus, loss of SORLA's Aß sorting function is a potential cause of AD in patients, and SORLA may be a new therapeutic target for AD drug development.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Proteínas Relacionadas con Receptor de LDL/metabolismo , Lisosomas/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Humanos , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Transgénicos

RESUMEN

We previously reported that glioma cells induce the expression of membrane-type 1 metalloproteinase (MT1-MMP or MMP-14) in tumor-associated microglia/macrophages and promote tumor growth, whereas MMP-14 expression in microglia under physiological conditions is very low. Here, we show that the increase in MMP-14 expression is also found in microglia/macrophages associated with neurodegenerative and neuroinflammatory pathologies in mouse models as well as in human biopsies or post-mortem tissue. We found that microglial/macrophage MMP-14 expression was upregulated in Alzheimer's disease tissue, in active lesions of multiple sclerosis, and in tissue from stage II stroke as well as in the corresponding mouse models for the human diseases. In contrast, we observed no upregulation for MMP-14 in microglia/macrophages in the early phase of stroke or in the corresponding mouse model, in human amyotrophic lateral sclerosis (ALS) tissue or in a mouse model of ALS as well as in human cases of acute brain trauma. These data indicate that MMP-14 expression is not a general marker for activated microglia/macrophages but is upregulated in defined stages of neuroinflammatory and neurodegenerative diseases and that there is generally a good match between mouse models and human brain pathologies.

Asunto(s)

Encéfalo/patología , Encefalitis/patología , Macrófagos/enzimología , Metaloproteinasa 14 de la Matriz/metabolismo , Microglía/enzimología , Enfermedades Neurodegenerativas/patología , Regulación hacia Arriba/fisiología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Encéfalo/metabolismo , Proteínas de Unión al Calcio , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Encefalitis/etiología , Glioma/complicaciones , Glioma/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Microfilamentos , Enfermedades Neurodegenerativas/etiología , Heridas Punzantes/complicaciones , Heridas Punzantes/patología

RESUMEN

In the brain, apolipoprotein E (APOE) delivers cholesterol-rich lipoproteins to neurons to support synaptogenesis and maintenance of synaptic connections. Three APOE alleles exist in the human population with ε4 being an Alzheimer disease (AD) risk gene and ε2 being protective relative to the common ε3 variant. Many hypotheses have been advanced concerning allele-specific effects of APOE on neurodegeneration including effects on Aß clearance, synaptic transmission, or neurotoxicity. Central to most proposed APOE functions is its interaction with receptors that mediate cellular uptake of this ligand. Several members of the LDL receptor gene family have been implicated as APOE receptors in the (patho)physiology of APOE in the brain, yet their specific modes of action in AD remain controversial. Recently, the pro-neurotrophin receptor sortilin has been identified as a novel APOE receptor in neurons. Ablation of sortilin expression in mice results in accumulation of APOE and Aß in the brain. Moreover, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/Aß complexes. Despite increased brain APOE levels, sortilin-deficient animals recapitulate anomalies in brain lipid homeostasis seen in APOE null mice, indicating functional deficiency in APOE uptake pathways. Taken together, these findings suggest a link between Aß catabolism and pro-neurotrophin signaling converging on this receptor pathway.

Asunto(s)

Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Neuronas/metabolismo , Animales

RESUMEN

Sorting-related receptor with A-type repeats (SORLA) is a sorting receptor for the amyloid precursor protein (APP) that prevents breakdown of APP into Aß peptides, a hallmark of Alzheimer's disease (AD). Several cytosolic adaptors have been shown to interact with the cytoplasmic domain of SORLA, thereby controlling intracellular routing of SORLA/APP complexes in cell lines. However, the relevance of adaptor-mediated sorting of SORLA for amyloidogenic processes in vivo remained unexplored. We focused on the interaction of SORLA with phosphofurin acidic cluster sorting protein 1 (PACS1), an adaptor that shuttles proteins between the trans-Golgi network (TGN) and endosomes. By studying PACS1 knockdown in neuronal cell lines and investigating transgenic mice expressing a PACS1-binding-defective mutant form of SORLA, we found that disruption of SORLA and PACS1 interaction results in the inability of SORLA/APP complexes to sort to the TGN in neurons and in increased APP processing in the brain. Loss of PACS1 also impairs the proper expression of the cation-independent mannose 6-phosphate receptor and its target cathepsin B, a protease that breaks down Aß. Thus, our data identified the importance of PACS1-dependent protein sorting for amyloidogenic-burden control via both SORLA-dependent and SORLA-independent mechanisms.

Asunto(s)

Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Relacionadas con Receptor de LDL/fisiología , Proteínas de Transporte de Membrana/fisiología , Proteínas de Transporte Vesicular/metabolismo , Secuencia de Aminoácidos , Animales , Encéfalo/enzimología , Catepsina B/biosíntesis , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen , Humanos , Proteínas Relacionadas con Receptor de LDL/química , Proteínas de Transporte de Membrana/química , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Neuronas/metabolismo , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Transporte de Proteínas , Receptor IGF Tipo 2/metabolismo , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/genética

RESUMEN

Apolipoprotein E (APOE) is the major risk factor for sporadic Alzheimer's disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-ß (Aß) peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors. Still, the receptors involved in this process remain controversial. Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aß complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aß in the brain and in aggravated plaque burden. Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/Aß complexes despite proper expression of other APOE receptors. Despite higher than normal brain APOE levels, sortilin-deficient animals display anomalies in brain lipid metabolism (e.g., accumulation of sulfatides) seen in APOE-deficient mice, indicating functional deficiency in cellular APOE uptake pathways. Together, our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo and suggest an intriguing link between Aß catabolism and pro-neurotrophin signaling converging on this receptor.

Asunto(s)

Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Neuronas/metabolismo , Animales , Apolipoproteínas E/metabolismo , Astrocitos/metabolismo , Ratones , Placa Amiloide/metabolismo

RESUMEN

Sortilin-related receptor with A-type repeats (SorLA, also known as LR11) has been implicated in Alzheimer's disease (AD). Thus, genetic studies associated SorLA gene variants with the risk of sporadic AD. Also, in vitro and in vivo studies showed that SorLA impairs processing of the amyloid-ß protein precursor (AßPP) to amyloid-ß. In particular, it has been found that loss of SorLA accelerates senile plaque deposition in mouse models overexpressing mutant forms of human AßPP and presenilin 1. Here we tested the possibility that SorLA deficiency also interferes with behavioral and neuropathological endpoints in an alternative murine AD model, the AD10 anti-nerve growth factor (NGF) mouse, in which amyloid-ß accumulation derives from the altered processing of endogenous AßPP. In addition to alterations in AßPP processing, AD10 mice also show cholinergic deficit and tau hyperphosphorylation resulting in behavioral deficits in learning and memory paradigms. We found that the loss of SorLA not only exacerbates early amyloid pathology but, at the same time, protects from cholinergic deficit and from early phospho-tau mislocalization. The results show that in the AD10 anti-NGF mouse model the AßPP processing-related aspects of neurodegeneration can be dissociated from those related to tau posttranslational processing and to cholinergic phenotypic maintenance by modulation of SorLA expression. We suggest that SorLA regulates different aspects of neurodegeneration in a complex way, supporting the hypothesis that SorLA expression might be critical not only for amyloid-related pathology but also for other cellular processes altered in AD.

Asunto(s)

Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Amiloidosis/genética , Neuronas Colinérgicas/metabolismo , Proteínas de Transporte de Membrana/genética , Receptores de LDL/genética , Proteínas tau/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/metabolismo , Amiloidosis/metabolismo , Amiloidosis/patología , Animales , Corteza Cerebral/patología , Corteza Cerebral/fisiología , Neuronas Colinérgicas/patología , Modelos Animales de Enfermedad , Femenino , Masculino , Aprendizaje por Laberinto/fisiología , Proteínas de Transporte de Membrana/deficiencia , Proteínas de Transporte de Membrana/metabolismo , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Degeneración Nerviosa/genética , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Fosforilación/fisiología , Receptor trkA/metabolismo , Receptores de LDL/deficiencia , Receptores de LDL/metabolismo

RESUMEN

OBJECTIVE: To identify SORL1 risk genotypes that determine receptor protein expression in the human brain. DESIGN: DNA, RNA, and proteins were extracted from brain autopsies of Alzheimer disease cases and used for SORL1 genotyping, RNA profiling, and SORLA protein quantification, respectively. SETTING: Specimens were provided by the MRC London Brain Bank for Neurodegenerative Diseases and the Netherlands Brain Bank. SUBJECTS: Brain autopsy material (frontal cortex) from 88 confirmed cases of sporadic Alzheimer disease. RESULTS: Our studies identified a SORL1 haplotype in the 3' gene region consisting of single-nucleotide polymorphisms rs1699102 and rs2070045 that is associated with poor receptor expression in the brain of patients with Alzheimer disease. These gene variations alter the SORL1 transcript sequence, resulting in a change from frequent to rare codon usage in the minor risk genotype. Studies in cultured cells confirm less efficient translation of the minor receptor transcripts into protein. CONCLUSION: Our findings suggest a functional mechanism that correlates SORL1 genotype with efficiency of receptor expression in the human brain.

Asunto(s)

Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Química Encefálica/genética , Proteínas Relacionadas con Receptor de LDL/biosíntesis , Proteínas de Transporte de Membrana/biosíntesis , Anciano , Alelos , Autopsia , Western Blotting , Encéfalo/patología , Células Cultivadas , ADN/genética , Ensayo de Inmunoadsorción Enzimática , Femenino , Variación Genética , Genotipo , Haplotipos , Humanos , Proteínas Relacionadas con Receptor de LDL/genética , Masculino , Proteínas de Transporte de Membrana/genética , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , ARN/genética , Medición de Riesgo

RESUMEN

The proteolytic breakdown of the amyloid precursor protein (APP) to neurotoxic amyloid-beta peptides in the brain has been recognized as a major pathological pathway in Alzheimer's disease (AD). Yet, the factors that control the processing of APP and their potential contribution to the common sporadic form of AD remain poorly understood. Here, we review recent findings from studies in patients and in animal models that led to the identification of a unique sorting receptor for APP in neurons, designated SORLA/SORL1, that emerges as a key player in amyloidogenic processing and as major genetic risk factor for AD.

Asunto(s)

Enfermedad de Alzheimer , Proteínas Relacionadas con Receptor de LDL/genética , Proteínas Relacionadas con Receptor de LDL/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Animales Modificados Genéticamente , Modelos Animales de Enfermedad , Humanos , Modelos Biológicos , Neuronas/metabolismo , Neuronas/patología , Transporte de Proteínas/genética

RESUMEN

Proper control of NaCl excretion in the kidney is central to bodily functions, yet many mechanisms that regulate reabsorption of sodium and chloride in the kidney remain incompletely understood. Here, we identify an important role played by the intracellular sorting receptor SORLA (sorting protein-related receptor with A-type repeats) in functional activation of renal ion transporters. We demonstrate that SORLA is expressed in epithelial cells of the thick ascending limb (TAL) of Henle's loop and that lack of receptor expression in this cell type in SORLA-deficient mice results in an inability to properly reabsorb sodium and chloride during osmotic stress. The underlying cellular defect was correlated with an inability of the TAL to phosphorylate Na(+)-K(+)-Cl(-) cotransporter 2 (NKCC2), the major sodium transporter in the distal nephron. SORLA functionally interacts with Ste-20-related proline-alanine-rich kinase (SPAK), an activator of NKCC2, and receptor deficiency is associated with missorting of SPAK. Our data suggest a novel regulatory pathway whereby intracellular trafficking of SPAK by the sorting receptor SORLA is crucial for proper NKCC2 activation and for maintenance of renal ion balance.

Asunto(s)

Riñón/enzimología , Proteínas de Transporte de Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de LDL/metabolismo , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Animales , Sistema Endocrino/metabolismo , Canales Epiteliales de Sodio/metabolismo , Homeostasis , Inmunohistoquímica , Iones/metabolismo , Riñón/citología , Riñón/metabolismo , Riñón/ultraestructura , Proteínas de Transporte de Membrana/química , Proteínas de Transporte de Membrana/deficiencia , Ratones , Modelos Biológicos , Canales de Potasio de Rectificación Interna/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Transporte de Proteínas , Receptores de LDL/química , Receptores de LDL/deficiencia , Sales (Química)/metabolismo , Intercambiador 3 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/metabolismo , Miembro 1 de la Familia de Transportadores de Soluto 12 , Fracciones Subcelulares/metabolismo , Extractos de Tejidos

RESUMEN

Sortilin-related receptor with A-type repeats (SORLA) is a sorting receptor that impairs processing of amyloid precursor protein (APP) to soluble (s) APP and to the amyloid beta-peptide in cultured neurons and is poorly expressed in patients with Alzheimer disease (AD). Here, we evaluated the consequences of Sorla gene defects on brain anatomy and function using mouse models of receptor deficiency. In line with a protective role for SORLA in APP metabolism, lack of the receptor results in increased amyloidogenic processing of endogenous APP and in aggravated plaque deposition when introduced into PDAPP mice expressing mutant human APP. Surprisingly, increased levels of sAPP caused by receptor deficiency correlate with pro-found stimulation of neuronal ERK signaling and with enhanced neurogenesis, providing in vivo support for neurotrophic functions of sAPP. Our data document a role for SORLA not only in control of plaque burden but also in APP-dependent neuronal signaling and suggest a molecular explanation for increased neurogenesis observed in some AD patients.

Asunto(s)

Envejecimiento/fisiología , Precursor de Proteína beta-Amiloide/metabolismo , Diferenciación Celular , Sistema de Señalización de MAP Quinasas , Proteínas de Transporte de Membrana/metabolismo , Neuronas/citología , Neuronas/metabolismo , Receptores de LDL/metabolismo , Animales , Electrofisiología , Activación Enzimática , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas de Transporte de Membrana/deficiencia , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Noqueados , Técnicas de Placa-Clamp , Receptores de LDL/deficiencia , Receptores de LDL/genética

RESUMEN

Leptin, via leptin receptors (Ob-R), regulates appetite and energy balance. Of the six isoforms of the receptor identified, so far, only the long form (Ob-Rb) can fully activate downstream signal transduction pathways. Although the expression and function of leptin receptors is well described in the adult brain, little is known about the ontogeny of leptin receptor system around the time of birth. In this study, the mRNA expression patterns of total leptin receptor, Ob-R, and the long signalling form of the receptor, Ob-Rb, were investigated in the brain of embryonic and newborn rats using in situ hybridisation and [125I]leptin binding. On embryonic day 18 (E18), Ob-R mRNA was detected in the choroid plexus and the ependymal layer of the third ventricle by in situ hybridisation. At E21, Ob-Rb mRNA was first observed in the arcuate and the ventral premammillary hypothalamic nuclei while at P3, receptor expression was also found in the dorsomedial nucleus. Other leptin target areas identified were the trigeminal ganglion, the thalamus and the hippocampus. Using quantitative receptor autoradiography specific [125I]leptin binding sites on the choroid plexus were found to increase with age in contrast to the ependymal layer of the third ventricle where levels decreased with age. Together these findings demonstrate that the leptin receptor system is differentially regulated during late gestation and early postnatal life in the rat.

Asunto(s)

Leptina/metabolismo , Prosencéfalo/embriología , Prosencéfalo/metabolismo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Animales , Animales Recién Nacidos , Autorradiografía , Femenino , Regulación del Desarrollo de la Expresión Génica , Edad Gestacional , Hibridación in Situ , Radioisótopos de Yodo , Leptina/farmacología , Embarazo , Prosencéfalo/crecimiento & desarrollo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Leptina