Adolfo Toledano-Díaz

Diversity and variability of the effects of nicotine on different cortical regions of the brain. Therapeutic and toxicological implications

Nicotine/nicotine agonists or allosteric modulators of nicotine receptors have been suggested as the most important therapeutic agents in the prevention and clinical control of cognitive impairment which characterize neuropsychiatric and neurodegenerative disorders such as schizophrenia, attention deficit/hyperactivity disorder and Alzheimers disease. Both clinical studies and animal experiments support the important role of the nicotinic systems in learning, different kind of memory and cognition. For development of nicotinic treatments we have a well characterized lead compound, nicotine. However, the neural nicotinic mechanisms underlying cognitive functions are not well known because the side effects of nicotine overdose have hindered the development of this therapeutical line. The new development of non-toxic, brain specific nicotine drugs need a full knowledge of these mechanism and a reevaluation of the nicotine effects. This review aims to analyze the different kind of effects of nicotine on the Central Nervous System (CNS), especially on the cortex and hippocampus. Nicotine effects are, theoretically and/or practically, of variable character depending on daily dose and time of treatment; on the subtype and density of the different nicotinic receptors existing in the distinct brain regions; on the processes of desensitization and tolerance of nicotinic receptors and on other neuronal factors. Nicotine produces the above mentioned activation of the cognitive functions acting directly or indirectly on cortical neurons. In some experiments, high doses of nicotine can impair memory. This substance induces increases in the glycolytic pathway and Krebs cycle of neurons, as well as brain blood flow. Nicotine also produces an increase in NGF immunoreactivity in frontoparietal cortex. All these neuronal changes may cause different positive effects such as neuroprotection, neuroplasticity and better performance of synaptic circuits. The benefit of other neuronal changes can be matter of discussion such as some modifications in synaptic transmission, the COX-2 increase in frontoparietal cortex and hippocampus or the changes in the antioxidant systems. Finally, other neuronal changes can be of negative effect such as the induction of apoptosis and oxidative stress (DNA damage, ROS and lipid peroxide increase). All these described effects explain both the beneficial and neurotoxic consequences of the activation of the nicotinic receptors. The diversity and variability of the nicotinic effects should take into account when nicotine agonists will be used as a possible cognitive treatment.

Effects of CX3CR1 and Fractalkine Chemokines in Amyloid Beta Clearance and p-Tau Accumulation in Alzheimer's Disease (AD) Rodent Models: Is Fractalkine a Systemic Biomarker for AD?

Microglia and astrocytes are the major source of cytokines in Alzheimer,s disease (AD). CX3CR1 is a delta chemokine receptor found in microglia and its neuronal ligand, Fractalkine, has two isoforms: an anchored-membrane isoform, and a soluble isoform. The reduced soluble fractalkine levels found in the brain (cortex/hippocampus) of aged rats, may be a consequence of neuronal loss. This soluble fractalkine maintains microglia in an appropiate state by interacting with CX3CR1. The ablation of the CX3CR1 gene in mice overexpressing human amyloid precursor protein (APP/PS-1) increased cytokine levels, enhanced Tau pathology and worsened behavioural performance in these mice. However, CX3CR1 deficiency resulted in a gene dose-dependent Aβ clearance in the brain, and induced microglial activation. In addition, CX3CR1 deficiency can have benefical effects by preventing neuronal loss in the 3xTg model. In fact, CX3CR1 deficiency increases microglial phagocytosome activity by inducing selective protofibrillar amyloid-beta phagocytosis in microglial cells in transgenic AD models. On the other hand, the fractalkine membrane isoform plays a differential role in amyloid beta clearance and Tau deposition. This anchored membrane FKN signalling might increase amyloid pathology while soluble fractalkine levels could prevent taupathies. However, in human AD, the only published study has reported higher systemic fractalkine levels in AD patients with cognitive impairment. In mouse models, inflammatory activation of microglia accelerates Tau pathology. Studies in transgenic mice with fractalkine null mice suggest that APP/PS-1 mice deficient for the anchored membrane-fractalkine isoform exhibited enhanced neuronal MAPT phosphorylation despite their reduced amyloid burden. The soluble fractalkine overexpression with adenoviral vectors reduced tau pathology and prevented neurodegeneration in a Tg4510 model of taupathy Finally, animals with Aβ (1-42) infused by lentivirus (cortex) or mice with the P301L mutation (frontotemporal dementia) had caspase-3 activation (8-fold) and higher proinflammatory TNF alpha levels and p-Tau deposits at 4 weeks postinfusion. Thus, the CX3CR1/Fractalkine axis regulates microglial activation, the clearance of amyloid plaque and plays a role in p-Tau intraneuronal accumulation in rodent models of AD.

Calretinin-immunopositive Cells and Fibers in the Cerebellar Cortex of Normal Sheep

Calretinin (CR)-immunopositive cells and fibers in the cerebellar cortex (vermal archicerebellum—lobules X and IX—and neocerebellum—lobules VIIb and VIII) of two and 4-year-old Manchega and Rasa Aragonesa sheep were studied. CR-immunoreactivity was seen in subsets of all neurons and afferent fibers described in the cerebellar cortex. Generally, immunopositive cells were seen in very high densities in lobules X and IX, and in low density in lobule VIIb. Apparently, all unipolar brush cells were CR-immunopositive and showed a greater variety of shape than had been reported in other species. CR-immunoreactivity of Purkinje cells was either absent or varied from low to medium intensity. Few granule cell perikarya were immunostained (<5%) but a large number of their axons were CR-immunopositive. Subsets of stellate and basket cells were CR-immunoreactive—quite different to what is seen in most of mammalian species. Strongly CR-immunopositive mossy and climbing fibers, isolated or grouped, were observed in all lobules. Although we found neither a difference in CR-immunoreactivity between the two breds of sheep, nor between the two ages examined, we observed important differences in CR-immunoreactivity between sheep and other mammalian species. Our observation of neuronal clusters and groups of fibers with very high CR-immunopositivity supports the idea of a heterogeneous species-specific functional organization for the cerebellar cortex within an apparent homogeneous histological structure maintained throughout mammalian evolution. The results also suggest that the varied levels of CR expression may be related to the specific functions of these immunopositive neurons and fibers rather than to a general neuroprotective role played by calretinin in the cerebellar cortex.

¿Existe la enfermedad de Alzheimer en todos los primates? Afección de Alzheimer en primates no humanos y sus implicaciones fisiopatológicas (I)

INTRODUCTION Many publications consider that Alzheimers disease (AD) is exclusive to the human species, and that no other animal species suffers from the disease. However, various studies have shown that some species can present with some of the defining characteristics of the human disease, including both neuropathological changes and cognitive-behavioural symptoms. DEVELOPMENT In this work, the results published (PubMed) on senile brain changes in non-human primates of different degrees of evolution, are reviewed. The neuropathological changes associated with the accumulation of amyloid or highly phosphorylated tau protein are rare outside the primate order, but in all the sub-orders, families, genera and species of non-human primates that have been studied, some senile individuals have shown amyloid accumulation in the brain. In fact, in some species the presence of these deposits in senility is constant. Changes related to the accumulation of tau protein are always of very little significance, and have been detected only in some non-human primate species, both little evolved and highly evolved. In different species of non-human primates, some types of cognitive-behavioural changes are more common in some senile individuals when compared with both normal adult individuals and other senile individuals of the species. The importance of determining the longevity of the species in different habitats (natural habitats, new habitats, semi-captivity, captivity) is stressed in these studies. CONCLUSIONS Morphological, histochemical and cognitive-behavioural features similar to those observed in elderly humans are present in senile non-human primates. Moreover, other characteristics seen in non-human primates could be indicative of a pathological «Alzheimer type» ageing.

Defective Insulin Signalling, Mediated by Inflammation, Connects Obesity to Alzheimer Disease; Relevant Pharmacological Therapies and Preventive Dietary Interventions

BACKGROUND Recent evidence suggests that obesity, besides being a risk factor for cardiovascular events, also increases the risk of Alzheimers disease. Insulin resistance is common in all cases of obesity and appears to be the linkage between both diseases. Obesity, often associated with excessive fat and sugar intake, represents a preclinical stage toward insulin resistance during which nutrition intervention is likely to have maximum effect. OBJECTIVE In this way, healthy lifestyles lifetime to prevent obesity-related modifiable risk factors such as inflammation, oxidative stress and metabolic disorders could be simultaneously beneficial for preserving cognition and controlling the Alzheimers disease. METHOD This review relates extensive research literature on facts linking nutrients and dietary patterns to obesity and Alzheimers disease. In addition briefly presents molecular mechanisms involved in obesity- induced insulin resistance and the contribution of peripheral inflammatory and defective insulin signalling pathways, as well as ectopic lipids accumulation to Alzheimers development through brain inflammation, neuronal insulin resistance, and cognitive dysfunction seen in Alzheimers disease. RESULTS The work relates current and emerging pharmacological and non-pharmacological therapies for the management of obesity, insulin resistance and Alzheimers considering them as disorders with common molecular features. CONCLUSION The findings of this review validate the importance of some nutritional interventions as possible approach to prevent or delay simultaneously progression of Alzheimers disease and obesity.

Brain local and regional neuroglial alterations in alzheimer¿s disease: Cell types, responses and implications

From birth to death, neurons are dynamically accompanied by neuroglial cells in a very close morphological and functional relationship. Three families have been classically considered within the CNS: astroglia, oligodendroglia and microglia. Many types/subtypes (including NGR2+ cells), with a wide variety of physiological and pathological effects on neurons, have been described using morphological and immunocytochemical criteria. Glio-glial, glio-neuronal and neuro-glial cell signaling and gliotransmission are phenomena that are essential to support brain functions. Morphofunctional changes resulting from the plasticity of all the glial cell types parallel the plastic neuronal changes that optimize the functionality of neuronal circuits. Moreover, neuroglia possesses the ability to adopt a reactive status (gliosis) in which, generally, new functions arise to improve and restore if needed the neural functionality. All these features make neuroglial cells elements of paramount importance when attempting to explain any physiological or pathological processes in the CNS, because they are involved in both, neuroprotection/neurorepair and neurodegeneration. There exist diverse and profound, regional and local, neuroglial changes in all involutive processes (physiological and pathological aging; neurodegenerative disorders, including Alzheimer ´s disease -AD-), but today, the exact meaning of such modifications (the modifications of the different neuroglial types, in time and place), is not well understood. In this review we consider the different neuroglial cells and their responses in order to understand the possible role they fulfill in pathogenesis, diagnosis and treatment (preventive or palliative) of AD. The existence of differentiated and/or concurrent pathogenic and neuro-protective/neuro-restorative astroglial and microglial responses is highlighted.

Changes Induced by Natural Scrapie in the Calretinin-Immunopositive Cells and Fibres of the Sheep Cerebellar Cortex

Calretinin (CR)-immunopositive cells and fibres in the cerebellar cortex (vermal archicerebellum and neocerebellum) of scrapie-affected, ARQ/ARQ, Rasa Aragonesa breed sheep were studied in comparison with healthy, young and aged, ARQ/ARQ, Rasa Aragonesa animals and with Manchega breed sheep. The scrapie-affected sheep showed signs of both cellular involution and hypertrophic/hyperimmunoreactive responses in all neuronal subtypes; the distribution of the neuronal subtypes in the archi- and neocerebellum, however, did not change compared with controls. The results suggest that the different CR expression and/or CR content of cerebellar cortical neurons in scrapie-affected sheep are more related to their specific functions than any neuroprotective response. The reduction in the cell density of some CR-immunopositive neuronal subsets (i.e. unipolar brush cells) is contradictory to the supposed neuroprotective role of the calcium binding protein CR. However, the hyperimmunoreactivity of many CR-immunopositive neuronal subsets (e.g. the Purkinje cells) suggests the involvement of an over-expression of CR (transitory or restricted to selected neurons) as an adaptative mechanism to fight against the neurodegeneration caused by this prion disease. The changes in the number of immunopositive cells and the hypertrophic/hyperimmunoreactive response seen in scrapie-affected and aged sheep suggests that some different and some similar mechanisms are at work in this disease and aging.

Variability in the Effects of Nicotine on Different Regions of the Brain: Changes in the Concentration of Superoxide Dismutase Isoforms

Previous studies have shown that rats subjected to subchronic treatment with nicotine experience changes in COX-2 (a marker of pro-inflammatory systems) and accumulate lipid hydroperoxides (a marker of oxidative stress) in the CNS (CNSMC, 2010; 10:180-206) (hippocampus, frontoparietal cortex and cerebellar cortex). Such changes are specific to each region since each contains different types of neuronal and glial cells with different nicotine receptors. They also differ in animals exposed to a source of oxidative stress, such as D-amphetamine. This paper discusses the changes in other markers of oxidative stress - the isozymes of superoxide dismutase Mn-SOD and Cu/Zn-SOD - in nicotine- and nicotine + D-amphetamine-treated rats. The biochemical and histochemical changes observed were specific to each region (in general very marked in the frontoparietal cortex and the hippocampus but less so in the cerebellar cortex) and each type of neuronal and glial cell. The SODs induced by nicotine may exert a neuroprotective effect via the reduction of oxidative stress. This might be beneficial in the treatment of neurodegenerative diseases. The fact that nicotine did not greatly increase the SODs in the rats treated with D-amphetamine may indicate that the effect of nicotine is partially or totally abolished in situations of oxidative stress. However, since ROS and lipid hydroperoxide levels are also reduced when nicotine is administered to such animals, it could be argued that nicotine is beneficial.