RESUMO
AIMS: KCL-286 is an orally available agonist that activates the retinoic acid receptor (RAR) ß2, a transcription factor which stimulates axonal outgrowth. The investigational medicinal product is being developed for treatment of spinal cord injury (SCI). This adaptive dose escalation study evaluated the tolerability, safety and pharmacokinetics and pharmacodynamic activity of KCL-286 in male healthy volunteers to establish dosing to be used in the SCI patient population. METHODS: The design was a double blind, randomized, placebo-controlled dose escalation study in 2 parts: a single ascending dose adaptive design with a food interaction arm, and a multiple ascending dose design. RARß2 mRNA expression was evaluated in white blood cells. RESULTS: At the highest single and multiple ascending doses (100 mg), no trends or clinically important differences were noted in the incidence or intensity of adverse events (AEs), serious AEs or other safety assessments with none leading to withdrawal from the study. The AEs were dry skin, rash, skin exfoliation, raised liver enzymes and eye disorders. There was an increase in mean maximum observed concentration and area under the plasma concentration-time curve up to 24 h showing a trend to subproportionality with dose. RARß2 was upregulated by the investigational medicinal product in white blood cells. CONCLUSION: KCL-286 was well tolerated by healthy human participants following doses that exceeded potentially clinically relevant plasma exposures based on preclinical in vivo models. Target engagement shows the drug candidate activates its receptor. These findings support further development of KCL-286 as a novel oral treatment for SCI.
Assuntos
Drogas em Investigação , Receptores do Ácido Retinoico , Humanos , Masculino , Voluntários Saudáveis , Relação Dose-Resposta a Droga , Área Sob a Curva , Método Duplo-CegoRESUMO
In the CNS, oligodendrocytes are responsible for myelin formation and maintenance. Following spinal cord injury, oligodendrocyte loss and an inhibitory milieu compromise remyelination and recovery. Here, we explored the role of retinoic acid receptor-beta (RARß) signaling in remyelination. Using a male Sprague Dawley rat model of PNS-CNS injury, we show that oral treatment with a novel drug like RARß agonist, C286, induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG2+ cells) in a decorin-mediated neuron-glia cross talk. Decorin promoted the activation of RARα in NG2+ cells by increasing the availability of the endogenous ligand RA. NG2+ cells synthesize RA, which is released in association with exosomes. We found that decorin prevents this secretion through regulation of the EGFR-calcium pathway. Using functional and pharmacological studies, we further show that RARα signaling is both required and sufficient for oligodendrocyte differentiation. These findings illustrate that RARß and RARα are important regulators of oligodendrocyte differentiation, providing new targets for myelination.SIGNIFICANCE STATEMENT This study identifies novel therapeutic targets for remyelination after PNS-CNS injury. Pharmacological and knock-down experiments show that the retinoic acid (RA) signaling promotes differentiation of oligodendrocyte precursor cells (OPCs) and remyelination in a cross talk between neuronal RA receptor-beta (RARß) and RARα in NG2+ cells. We show that stimulation of RARα is required for the differentiation of OPCs and we describe for the first time how oral treatment with a RARß agonist (C286, currently being tested in a Phase 1 trial, ISRCTN12424734) leads to the endogenous synthesis of RA through retinaldehyde dehydrogenase 2 (Raldh2) in NG2 cells and controls exosome-associated-RA intracellular levels through a decorin-Ca2+ pathway. Although RARß has been implicated in distinct aspects of CNS regeneration, this study identifies a novel function for both RARß and RARα in remyelination.
Assuntos
Exossomos/metabolismo , Bainha de Mielina/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Receptores do Ácido Retinoico/agonistas , Traumatismos da Medula Espinal/tratamento farmacológico , Tretinoína/metabolismo , Animais , Decorina/metabolismo , Receptores ErbB/metabolismo , Bainha de Mielina/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/metabolismoRESUMO
Neuronal regeneration is a highly energy-demanding process that greatly relies on axonal mitochondrial transport to meet the enhanced metabolic requirements. Mature neurons typically fail to regenerate after injury, partly because of mitochondrial motility and energy deficits in injured axons. Retinoic acid receptor (RAR)-ß signaling is involved in axonal and neurite regeneration. Here we investigate the effect of RAR-ß signaling on mitochondrial trafficking during neurite outgrowth and find that it enhances their proliferation, speed, and movement toward the growing end of the neuron via hypoxia-inducible factor 1α signaling. We also show that RAR-ß signaling promotes the binding of the mitochondria to the anchoring protein, glucose-related protein 75, at the growing tip of neurite, thus allowing them to provide energy and metabolic roles required for neurite outgrowth.-Trigo, D., Goncalves, M. B., Corcoran, J. P. T. The regulation of mitochondrial dynamics in neurite outgrowth by retinoic acid receptor ß signaling.
Assuntos
Dinâmica Mitocondrial/fisiologia , Crescimento Neuronal/fisiologia , Receptores do Ácido Retinoico/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Células Cultivadas , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/fisiologia , Camundongos , Dinâmica Mitocondrial/efeitos dos fármacos , Naftalenos/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Receptores do Ácido Retinoico/agonistasRESUMO
Retinoic acid receptors (RARs) α, ß, and γ are members of the nuclear receptor superfamily. Compounds which bind to and activate the RARs are termed retinoids which regulate a wide variety of biological processes such as vertebrate embryonic morphogenesis and organogenesis, cell growth arrest, differentiation, and apoptosis, as well as their disorders. Although many synthetic selective RARα, RARß, and RARγ agonists have been designed and prepared, these have generally been lipophilic acids without good drug-like properties and with low oral bioavailability. Recently this has been changing and drug design approaches to highly potent and selective RARα and RARß agonists with low lipophilicity that are orally bioavailable and less toxic have been developed, that have a range of potential therapeutic uses. This review covers these new advances.
Assuntos
Ácidos Carboxílicos/farmacologia , Desenho de Fármacos , Receptores do Ácido Retinoico/agonistas , Receptor alfa de Ácido Retinoico/agonistas , Administração Oral , Disponibilidade Biológica , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/metabolismo , Humanos , Estrutura MolecularRESUMO
Oxadiazole replacement of an amide linkage in an RARα agonist template 1, followed by lead optimisation, has produced a highly potent and selective RARß agonist 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (10) with good oral bioavailability in the rat and dog. This molecule increases neurite outgrowth in vitro and induces sensory axon regrowth in vivo in a rodent model of avulsion and crush injury, and thus has the potential for the treatment of nerve injury.
Assuntos
Oxidiazóis/química , Receptores do Ácido Retinoico/agonistas , Administração Oral , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Locomoção/efeitos dos fármacos , Células Madin Darby de Rim Canino , Crescimento Neuronal/efeitos dos fármacos , Traumatismos do Nervo Óptico/tratamento farmacológico , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Ratos , Receptores do Ácido Retinoico/metabolismo , Relação Estrutura-AtividadeRESUMO
Stimulation of retinoic acid (RA) mediated signalling pathways following neural injury leads to regeneration in the adult nervous system and numerous studies have shown that the specific activation of the retinoic acid receptor ß (RARß) is required for this process. Here we identify a novel mechanism by which neuronal RARß activation results in the endogenous synthesis of RA which is released in association with exosomes and acts as a positive cue to axonal/neurite outgrowth. Using an established rodent model of RARß induced axonal regeneration, we show that neuronal RARß activation upregulates the enzymes involved in RA synthesis in a cell specific manner; alcohol dehydrogenase7 (ADH7) in neurons and aldehyde dehydrogenase 2 (Raldh2) in NG2 expressing cells (NG2+ cells). These release RA in association with exosomes providing a permissive substrate to neurite outgrowth. Conversely, deletion of Raldh2 in the NG2+ cells in our in vivo regeneration model is sufficient to compromise axonal outgrowth. This hitherto unidentified RA paracrine signalling is required for axonal/neurite outgrowth and is initiated by the activation of neuronal RARß signalling.
Assuntos
Antígenos/metabolismo , Exossomos/metabolismo , Regeneração Nervosa/fisiologia , Neuroglia/metabolismo , Crescimento Neuronal/fisiologia , Proteoglicanas/metabolismo , Tretinoína/metabolismo , Aldeído Oxirredutases/metabolismo , Animais , Transporte Biológico/fisiologia , Células Cultivadas , Medula Cervical/metabolismo , Medula Cervical/patologia , Técnicas de Cocultura , Modelos Animais de Doenças , Exossomos/patologia , Masculino , Camundongos , Neuroglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Ratos Sprague-Dawley , Receptores do Ácido Retinoico/metabolismo , Retinal Desidrogenase/metabolismo , Raízes Nervosas Espinhais/lesões , Raízes Nervosas Espinhais/metabolismo , Raízes Nervosas Espinhais/patologiaRESUMO
A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARß, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARß (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.
Assuntos
Aminobenzoatos/química , Benzoatos/química , Desenho de Fármacos , Receptor alfa de Ácido Retinoico/agonistas , Tetra-Hidronaftalenos/química , Administração Oral , Aminobenzoatos/farmacocinética , Aminobenzoatos/toxicidade , Animais , Benzoatos/farmacocinética , Benzoatos/toxicidade , Células COS , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Meia-Vida , Células Hep G2 , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Ratos , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico/metabolismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/farmacocinética , Tetra-Hidronaftalenos/toxicidade , Receptor gama de Ácido RetinoicoRESUMO
Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor ß (RARß) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)-CNS transition of regrown axons. RARß agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, in RARß-agonist-treated neurons, PTEN activity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect of RARß signaling, both neuronal and neuronal-glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs. SIGNIFICANCE STATEMENT: Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Here, we identify a single target, neuronal retinoic acid receptor ß (RARß), which modulates these two aspects of the postinjury physiological response. Activation of RARß in the neuron inactivates phosphatase and tensin homolog and induces its transfer into the astrocytes in small vesicles, where it prevents scar formation. This may open new therapeutic avenues for SCIs.
Assuntos
Astrócitos/metabolismo , Cicatriz/metabolismo , Exossomos/metabolismo , Neuroglia/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Receptores do Ácido Retinoico/fisiologia , Regeneração da Medula Espinal/fisiologia , Animais , Células Cultivadas , Cicatriz/prevenção & controle , Masculino , Camundongos , Neuroglia/patologia , Neurônios/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/fisiologiaRESUMO
The retinoic acid receptor (RAR) α system plays a key role in the adult brain, participating in the homeostatic control of synaptic plasticity, essential for memory function. Here we show that RARα signalling is down-regulated by amyloid beta (Aß), which inhibits the synthesis of the endogenous ligand, retinoic acid (RA). This results in the counteraction of a variety of RARα-activated pathways that are key in the aetiopathology of Alzheimer's disease (AD) but which can be reversed by an RARα agonist. RARα signalling improves cognition in the Tg2576 mice, it has an anti-inflammatory effect and promotes Aß clearance by increasing insulin degrading enzyme and neprilysin activity in both microglia and neurons. In addition, RARα signalling prevents tau phosphorylation. Therefore, stimulation of the RARα signalling pathway using a synthetic agonist, by both clearing Aß and counteracting some of its toxic effects, offers therapeutic potential for the treatment of AD.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Receptor X Retinoide alfa/agonistas , Tretinoína/metabolismo , Animais , Benzoatos/farmacologia , Cognição/efeitos dos fármacos , Regulação para Baixo , Insulisina/metabolismo , Camundongos , Microglia/metabolismo , Neprilisina/metabolismo , Neurônios/metabolismo , Receptor X Retinoide alfa/metabolismo , Transdução de Sinais , Tetra-Hidronaftalenos/farmacologiaRESUMO
We show here the role of retinoic acid receptor (RAR) beta and alpha signalling in proliferation and differentiation of endogenous adult forebrain neural progenitor cells (NPCs). RARbeta activation stimulates Sonic hedgehog signalling (Shh), and induces the proliferation of the NPCs. They can be induced to become Doublecortin (DCX) expressing migrating neuroblasts by RARalpha signalling, some of which differentiate into cholinergic neurons. The same signalling pathways cause the proliferation of embryonic forebrain NPCs. These cells express glial fibrillary acidic protein (GFAP) and are predominantly uni/bipolar, two characteristics of neuronal progenitor cells. We further show that fibroblast growth factor (FGF) signalling, induces the expression of the retinoic acid degrading enzyme cytochrome P450 (cyp) 26a1, and that one of its products, 4-oxo-RA, mimics the action of the RARalpha agonist in the differentiation of the NPCs into cholinergic neurons.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Proteínas Hedgehog/metabolismo , Neurônios/fisiologia , Receptores do Ácido Retinoico/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/fisiologia , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Inibidores Enzimáticos/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Proteínas Hedgehog/genética , Imidazóis/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/citologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Prosencéfalo/citologia , Pirróis/metabolismo , Ratos , Ratos Wistar , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico , Células-Tronco/citologia , Tretinoína/análogos & derivados , Tretinoína/química , Tretinoína/metabolismoRESUMO
After spinal cord injury in the adult mammal, axons do not normally regrow and this commonly leads to paralysis. Retinoic acid (RA) can stimulate neurite outgrowth in vitro of both the embryonic central and peripheral nervous system, via activation of the retinoic acid receptor (RAR) beta2. We show here that regions of the adult CNS, including the cerebellum and cerebral cortex, express RARbeta2. We show that when cerebellar neurons are grown in the presence of myelin-associated glycoprotein (MAG) which inhibits neurite outgrowth, RARbeta can be activated in a dose dependent manner by a RARbeta agonist (CD2019) and neurite outgrowth can occur via phosphoinositide 3-kinase (PI3K) signalling. In a model of spinal cord injury CD2019 also acts through PI3K signalling to induce axonal outgrowth of descending corticospinal fibres and promote functional recovery. Our data suggest that RARbeta agonists may be of therapeutic potential for human spinal cord injuries.
Assuntos
Axônios/efeitos dos fármacos , Naftalenos/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Axônios/fisiologia , Células Cultivadas , Cerebelo/efeitos dos fármacos , Cerebelo/fisiopatologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Glicoproteína Associada a Mielina/metabolismo , Naftalenos/administração & dosagem , Naftalenos/agonistas , Naftalenos/metabolismo , Regeneração Nervosa/fisiologia , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Fármacos Neuroprotetores/administração & dosagem , Tratos Piramidais/efeitos dos fármacos , Tratos Piramidais/fisiopatologia , Ratos , Recuperação de Função Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/fisiopatologiaRESUMO
Neuropathic pain (NP) is associated with profound gene expression alterations within the nociceptive system. DNA mechanisms, such as epigenetic remodeling and repair pathways have been implicated in NP. Here we have used a rat model of peripheral nerve injury to study the effect of a recently developed RARß agonist, C286, currently under clinical research, in NP. A 4-week treatment initiated 2 days after the injury normalized pain sensation. Genome-wide and pathway enrichment analysis showed that multiple mechanisms persistently altered in the spinal cord were restored to preinjury levels by the agonist. Concomitant upregulation of DNA repair proteins, ATM and BRCA1, the latter being required for C286-mediated pain modulation, suggests that early DNA repair may be important to prevent phenotypic epigenetic imprints in NP. Thus, C286 is a promising drug candidate for neuropathic pain and DNA repair mechanisms may be useful therapeutic targets to explore.
RESUMO
Many studies have shown a role of retinoid signalling in neurite outgrowth in vitro, and that the retinoic acid receptor (RAR) beta2 is critical for this process. We show here that RARbeta2 is expressed predominantly in dorsal root ganglia (DRG) neuronal subtypes that express neurofilament (NF) 200 and calcitonin gene-related peptide (CGRP), and that these neurons extend neurites in response to RA. We demonstrate that retinoid signalling has a role in neurite outgrowth in vivo, by showing that in a peripheral nerve crush model there is less neurite outgrowth from RARbeta null DRG compared to wild-type. We identify sonic hedgehog (Shh) as a downstream target of the RARbeta2 signalling pathway as it is expressed in the injured DRG of wild-type but not RARbeta null mice. This regulation is direct as when RARbeta2 is overexpressed in adult motoneurons Shh is induced in them. Finally we show that Shh alone cannot induce neurite outgrowth but potentiates RARbeta2 signalling in this process.
Assuntos
Proteínas Hedgehog/metabolismo , Fator de Crescimento Neural/fisiologia , Neuritos/metabolismo , Receptores do Ácido Retinoico/fisiologia , Transdução de Sinais , Tretinoína/fisiologia , Animais , Células Cultivadas , Gânglios Espinais , Proteínas Hedgehog/fisiologia , Técnicas In Vitro , Camundongos , Camundongos Knockout , Modelos Biológicos , Neuritos/efeitos dos fármacos , Neuritos/fisiologia , Nervos Periféricos/fisiologia , Sistema Nervoso Periférico/metabolismo , Sistema Nervoso Periférico/fisiologia , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismoRESUMO
By culturing neural progenitor cells in the presence of retinoid receptor agonists, we have defined the components of the retinoid-signalling pathway that are important for the birth and maintenance of neuronal cells. We provide evidence that depending on the order and combination of retinoid receptors activated, different neuronal cells are obtained. Astrocytes and oligodendrocytes are predominantly formed in the presence of activated retinoic acid receptor (RAR) alpha, whereas motoneurons are formed when RARbeta is activated. We have looked at the regulation of two transcription factors islet-1/2 which are involved in neuronal development. We find that activated RARbeta up-regulates islet-1 expression, whereas activation of RARalpha can either act in combination with RARbeta signalling to maintain islet-1 expression or induce islet-2 expression in the absence of activated RARbeta. RARgamma cannot directly regulate islet-1/2 but can down-regulate RARbeta expression, which results in loss of islet-1 expression. We finally show that activated RARalpha is one of the final steps required for a mature motoneuron phenotype.
Assuntos
Células-Tronco Multipotentes/metabolismo , Neurônios/metabolismo , Retinoides/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas com Homeodomínio LIM , Modelos Neurológicos , Neurônios Motores/citologia , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fenótipo , Ratos , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/metabolismo , Transdução de Sinais , Fatores de Transcrição , Tretinoína/farmacologiaRESUMO
We have disrupted the retinoid signalling pathway in adult rats by a dietary deficiency of vitamin A. After 1 year of this dietary deficiency, there was a deposition of amyloid beta in the cerebral blood vessels. There is a downregulation of retinoic acid receptor alpha in the forebrain neurons of the retinoid-deficient rats and a loss of choline acetyl transferase expression, which precedes amyloid beta deposition. In neocortex of pathology samples of patients with Alzheimer's disease, the same retinoic acid receptor alpha deficit in the surviving neurons was observed. We have identified the retinoid-synthesizing enzymes involved in this process, retinaldehyde dehydrogenase-2 and class IV alcohol dehydrogenase, only the former is downregulated in patients with Alzheimer's disease. This suggests that retinoids are important for the maintenance of the adult nervous system and their loss may in part play a role in Alzheimer's disease.