An approach to the effects of longevity, sexual maturity, and reproduction on telomere length and oxidative stress in different Psittacidae species.

Introduction: Aging is a multifactorial process that includes molecular changes such as telomere shortening. Telomeres shorten progressively with age in vertebrates, and their shortening rate has a significant role in determining the lifespan of a species. However, DNA loss can be enhanced by oxidative stress. The need for novel animal models has recently emerged as a tool to gather more information about the human aging process. Birds live longer than other mammals of the same size, and Psittacidae species are the most persevering of them, due to special key traits. Methods: We aimed to determine telomere length by qPCR, and oxidative stress status using colorimetric and fluorescence methods in different species of the order Psittaciformes with different lifespans. Results: We found that telomeres shorten with age for both long- and short-lived birds (p < 0.001 and p = 0.004, respectively), with long-lived birds presenting longer telomeres than short-lived ones (p = 0.001). In addition, short-lived birds accumulated more oxidative stress products than long-lived birds (p = 0.013), who showed a better antioxidant capacity (p < 0.001). Breeding was found related to telomere shortening in all species (p < 0.001 and p = 0.003 for long- and short-lived birds). Short-lived birds, especially breeding females, increased their oxidative stress products when breeding (p = 0.021), whereas long-lived birds showed greater resistance and even increased their antioxidant capacity (p = 0.002). Conclusion: In conclusion, the relationship between age and telomere length in Psittacidae was verified. The influence of breeding increased cumulative oxidative damage in short-lived species, while long-lived species may counteract this damage.

Sexual Dimorphism in the Behavioral Responses and the Immunoendocrine Status in d-Galactose-Induced Aging.

For almost 20 years, chronic systemic d-galactose, a monosaccharide abundantly present in milk products, fruits, and vegetables, has been used as a tool to achieve models of accelerated aging. Its neurotoxicity, induced by abnormal accumulation of reactive oxygen species and advanced glycation end products, has been widely reported. However, behavioral outcomes are still controversial and little is known about sex-dependent vulnerability. We performed a comprehensive behavioral and multifunctional screening of the chronic effects of low (50 mg/kg) and high (100 mg/kg) doses of d-galactose in 6-month-old male and female gold-standard C57BL/6 mice. Twelve classical tests with convergent validity analyzed sensorimotor, emotional and cognitive domains, indicating the existence of thresholds of response. Distinct vulnerability patterns were found in a selective sex- and dose-dependent manner. In males, d-galactose induced sensorimotor impairment and immunoendocrine senescence, but the low dose resulted in improved learning and memory. Oppositely, d-galactose-treated females exhibited a dose-dependent worse motor and spatial learning, but improved memory. Behavioral outcome items point at distinct neuronal substrates underlying the functional capacity of d-galactose-treated animals to meet task-dependent performance demands. They support that males and females can be regarded as two exceptional natural scenarios to study the functional interplay in the cross talk of homeostatic networks in aging.

Terapias antienvejecimiento aplicadas a la enfermedad de Alzheimer / Anti-ageing therapies in Alzheimer's disease

La enfermedad de Alzheimer es la causa más común de demencia en la población anciana. Actualmente no hay tratamientos efectivos para prevenir o retrasar el curso natural de dicha enfermedad. Numerosos estudios han proporcionado información de los procesos moleculares que subyacen en el envejecimiento biológico y, quizás más importante aún, de las posibles intervenciones para retrasar el envejecimiento y promover la longevidad saludable en sistemas modelo de laboratorio. La cuestión principal tratada en esta revisión es si una intervención que tiene propiedades antienvejecimiento puede alterar la aparición y/o progresión de la enfermedad de Alzheimer, una enfermedad en la que la edad es el mayor factor de riesgo. Diferentes intervenciones antienvejecimiento han demostrado prevenir (y posiblemente restaurar en algunos casos) varios parámetros reconocidos como síntomas centrales para el desarrollo de la enfermedad de Alzheimer. Además, se están dando los primeros pasos hacia la traslación de estos descubrimientos de laboratorio a aplicaciones clínicas (AU)

Alzheimer's disease is the most common cause of dementia in the elderly population. Currently, there are no effective treatments to prevent or delay the natural course of the disease. Numerous studies have provided information about the molecular processes underlying biological ageing and, perhaps more importantly, potential interventions to slow ageing and promote healthy longevity in laboratory model systems. The main issue addressed in this review is whether an intervention that has anti-ageing properties can alter the appearance and/or progression of Alzheimer's disease, a disease in which age is the biggest risk factor. Different anti-ageing interventions have been shown to prevent (and in some cases possibly restore) several parameters recognised as central symptoms to the development of Alzheimer's disease. In addition, they are taking the first steps towards translating these laboratory discoveries into clinical applications (AU)

[Anti-ageing therapies in Alzheimer's disease]. / Terapias antienvejecimiento aplicadas a la enfermedad de Alzheimer.

Alzheimer's disease is the most common cause of dementia in the elderly population. Currently, there are no effective treatments to prevent or delay the natural course of the disease. Numerous studies have provided information about the molecular processes underlying biological ageing and, perhaps more importantly, potential interventions to slow ageing and promote healthy longevity in laboratory model systems. The main issue addressed in this review is whether an intervention that has anti-ageing properties can alter the appearance and/or progression of Alzheimer's disease, a disease in which age is the biggest risk factor. Different anti-ageing interventions have been shown to prevent (and in some cases possibly restore) several parameters recognised as central symptoms to the development of Alzheimer's disease. In addition, they are taking the first steps towards translating these laboratory discoveries into clinical applications.

Choroid plexus dysfunction impairs beta-amyloid clearance in a triple transgenic mouse model of Alzheimer's disease.

Compromised secretory function of choroid plexus (CP) and defective cerebrospinal fluid (CSF) production, along with accumulation of beta-amyloid (Aß) peptides at the blood-CSF barrier (BCSFB), contribute to complications of Alzheimer's disease (AD). The AD triple transgenic mouse model (3xTg-AD) at 16 month-old mimics critical hallmarks of the human disease: ß-amyloid (Aß) plaques and neurofibrillary tangles (NFT) with a temporal- and regional- specific profile. Currently, little is known about transport and metabolic responses by CP to the disrupted homeostasis of CNS Aß in AD. This study analyzed the effects of highly-expressed AD-linked human transgenes (APP, PS1 and tau) on lateral ventricle CP function. Confocal imaging and immunohistochemistry revealed an increase only of Aß42 isoform in epithelial cytosol and in stroma surrounding choroidal capillaries; this buildup may reflect insufficient clearance transport from CSF to blood. Still, there was increased expression, presumably compensatory, of the choroidal Aß transporters: the low density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end product (RAGE). A thickening of the epithelial basal membrane and greater collagen-IV deposition occurred around capillaries in CP, probably curtailing solute exchanges. Moreover, there was attenuated expression of epithelial aquaporin-1 and transthyretin (TTR) protein compared to Non-Tg mice. Collectively these findings indicate CP dysfunction hypothetically linked to increasing Aß burden resulting in less efficient ion transport, concurrently with reduced production of CSF (less sink action on brain Aß) and diminished secretion of TTR (less neuroprotection against cortical Aß toxicity). The putative effects of a disabled CP-CSF system on CNS functions are discussed in the context of AD.

Octodon degus: a strong attractor for Alzheimer research.

The most popular animal models of Alzheimer's disease (AD) are transgenic mice expressing human genes with known mutations which do not represent the most abundant sporadic form of the disease. An increasing number of genetic, vascular and psychosocial data strongly support that the Octodon degus, a moderate-sized and diurnal precocial rodent, provides a naturalistic model for the study of the early neurodegenerative process associated with sporadic AD. In this minireview we describe and analyze the risk factors that contribute to Alzheimer-like characteristics in the degus, following recent publications, and establish some guidelines for future studies in this model of natural aging associated with the disease. Given the heterogeneity of current data derived from the diverse transgenic animal models of AD, now may be the time for the degus to become a strong attractor for academic research labs and companies involved with AD. This may help to understand the mechanisms responsible for the early neurodegenerative process associated with this devastating disease.

Terapia génica no invasiva en enfermedades neurológicas / Non invasive gene therapy in neurological diseases

Introduction. Brain gene therapy consists of introducing nucleic acids into nerve tissue whose expression may prove to betherapeutically useful. This genetic material is indirectly introduced by means of non invasive gene therapy into the bloodthereby avoiding its direct injection into the brain and the damage to the blood brain barrier.Aim. The different non invasive vectors and means of gene transfer to the central nervous system will be discussed.Development. There has been a remarkable breakthrough in recent years in non invasive gene transfer strategies into thecentral nervous system. The development of new serotypes of adenoassociated vectors, such as AAV9, and of functionalizednanoparticles, such as pegylated immunoliposomes, polymeric nanoparticles, pegylated nanoparticles, dendrimers, fullerens,as well as specific transporters specific to the low density lipoprotein receptor family, means that it is now possible tointroduce and express gene material in nerve tissue following peripherical administration of the above mentioned vectors.Conclusions. Non invasive gene therapy entails exciting new perspectives for the treatment of the numerous neurologicaldiseases for which there are no effective pharmacological treatments. Studies already performed on animals have provedto be highly promising and it is likely that, in the next few years, they will give rise to non invasive gene therapy procedureswhich will be useful and safe for treating patients (AU)

Introducción. La terapia génica cerebral consiste en la introducción de ácidos nucleicos en el tejido nervioso cuya expresiónpueda resultar de utilidad terapéutica. Mediante la terapia génica no invasiva, este material genético es introducido indirectamentepor vía sanguínea, evitando su inyección directa en el parénquima cerebral y el daño de la barrera hematoencefálica.Objetivo. Discutir los diferentes vectores y vías no invasivas de transferencia génica al sistema nervioso central.Desarrollo. En los últimos años se ha producido un giro espectacular en las estrategias para la transferencia génica no invasivadel sistema nervioso central. El desarrollo de nuevos serotipos de vectores adenoasociados, como AAV9, de una gama denanopartículas funcionalizadas, como inmunoliposomas pegilados, nanopartículas poliméricas, nanopartículas pegiladas,dendrímeros, fulerenos, así como de transportadores específicos de la familia de receptores de lipoproteína de baja densidad,permite introducir y expresar material génico en el tejido nervioso tras la administración periférica de dichos vectores.Conclusiones. La terapia génica no invasiva supone nuevas y excitantes perspectivas para el tratamiento de las numerosasenfermedades neurológicas para las cuales no existen tratamientos farmacológicos efectivos. Los estudios ya realizadosen animales resultan altamente prometedores y es probable que, en los próximos años, den lugar a procedimientos de terapia génica útiles y seguros para su uso en pacientes (AU)

Glial regulation of nonsynaptic extracellular glutamate in the substantia nigra.

GLU is the main neurotransmitter in the brain, where it induces a synaptic excitatory action. There is recent evidence for an extracellular nonsynaptic GLU (EnS-GLU) pool in different brain nuclei that, released from glial cells, may act on extrasynaptic GLU receptors of cells located far from the position in which it was released. In the present work, the EnS-GLU pool was studied with microdialysis in the rat substantia nigra (SN). We observed an EnS-GLU pool that increased in a Ca2+-dependent manner during cell depolarization. The selective alteration of with methionine sulfoximide (MSO) and fluorocitrate induced marked modifications in EnS-GLU suggesting that EnS-GLU is dependent on glial cells. Glutamine administration increased GLU, suggesting that neurons are also involved in EnS-GLU modulation. GLU administered in the rostral SN showed a long-distance diffusion to the caudal SN. The ionotropic GLU receptors agonist N-methyl-D-aspartate and kainate and the metabotropic GLU receptors agonist ACPD increased EnS-GLU and decreased extracellular glutamine. Taken together, these data indicate that nigral glia releases GLU, which probably performs a volume transmitter role.

Extracellular taurine in the substantia nigra: taurine-glutamate interaction.

Taurine has been proposed as an inhibitory transmitter in the substantia nigra (SN), but the mechanisms involved in its release and uptake remain practically unexplored. We studied the extracellular pool of taurine in the rat's SN by using microdialysis methods, paying particular attention to the taurine-glutamate (GLU) interaction. Extracellular taurine increased after cell depolarization with high-K(+) in a Ca(2+)-dependent manner, being modified by the local perfusion of GLU, GLU receptor agonists, and zinc. Nigral administration of taurine increased the extracellular concentration of gamma-aminobutyric acid (GABA) and GLU, the transmitters of the two main inputs of the SN. The modification of the glial metabolism with fluocitrate and L-methionine sulfoximine also changed the extracellular concentration of taurine. The complex regulation of the extracellular pool of taurine, its interaction with GABA and GLU, and the involvement of glial cells in its regulation suggest a volume transmission role for taurine in the SN.