Rehabilitating a brain with Alzheimer’s: a proposal

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, originating sporadically in the population aged over 65 years, and advanced age is the principal risk factor leading to AD development. In spite of the large amount of research going on around the globe and all the information now available about AD, there is still no origin or triggering process known so far. Drugs approved for the treatment of AD include tacrine, donepezil, rivastigmine, galantamine, and memantine. These may delay or slow down the degenerative process for a while, but they can neither stop nor reverse its progression. Because that this might be due to a lack of effect of these drugs on degenerating neurons, even when they are able to potentiate the brain in nondegenerative conditions, we propose here an alternative therapy consisting of initial repair of neuronal membranes followed by conventional drug therapies. The rehabilitation of neurons in a degeneration process would enable the drugs to act more effectively on them and improve the effects of treatment in AD patients

Análisis de la expresión de tau, APP, nicastrina, betasecretasa y genes asociados, en leucocitos, como marcadores de la enfermedad de Alzheimer

Tau, APP, nicastrina y ß-secretasa son las principales moléculas implicadas en la fisiopatología de la enfermedad de Alzheimer, al ser directamente responsables de la generación de las placas neuríticas y los ovillos neurofibrilares. Diversas variantes genéticas y condiciones médicas comunes en la población adulta han sido asociadas con un riesgo incrementado de padecer la enfermedad. Existe también una respuesta inmune periférica a los cambios que ocurren en el cerebro con Alzheimer, aunque poco se conoce sobre el comportamiento de tau, APP, nicastrina y ß-secretasa en células no neuronales..

Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we performed an exploratory study of the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. Overall, we observed relatively weak associations (p < 1 × 10-4) with BP phenotypes within immune-related genes. Network and functional enrichment analyses of the top findings from the association analyses of Li response variables showed an overrepresentation of pathways participating in cell adhesion and intercellular communication. These appeared to converge on the well-known Li-induced inhibition of GSK-3β. Association analyses of age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation suggested modest contributions of genes such as RTN4, XKR4, NRXN1, NRG1/3 and GRK5 to disease characteristics. PGS analyses returned weak associations (p < 0.05) between inflammation markers and the studied BP phenotypes. Our results suggest a modest relationship between immunity and clinical features in BP. More research is needed to assess the potential therapeutic relevance

Dysregulation of TLR5 and TAM Ligands in the Alzheimer's Brain as Contributors to Disease Progression.

peer reviewedThe hypothesis that accumulation of beta-amyloid (Aβ) species in the brain represents a major event in Alzheimer's disease (AD) pathogenesis still prevails; nevertheless, an array of additional pathological processes contributes to clinical presentation and disease progression. We sought to identify novel targets for AD within genes related to amyloid precursor protein (APP) processing, innate immune responses, and the catecholamine system. Through a series of bioinformatics analyses, we identified TLR5 and other genes involved in toll-like receptor (TLR) signaling as potential AD targets. It is believed that Aβ species induce activation of microglia and astrocytes in AD, with a negative impact on disease progression. The TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases plays pivotal roles in limiting inflammatory responses upon TLR stimulation, for which we further studied their implication in the TLR5 alterations observed in AD. We validated the up-regulation of TLR5 in the frontal cortex of moderate AD cases. In addition, we observed up-regulation of the TAM ligands protein S (PROS1), galectin-3 (LGALS3), and Tulp-1. Furthermore, we identified an association of the TAM ligand GAS6 with AD progression. In THP-1 cells, co-stimulation with Aβ and flagellin for 24 h induced up-regulation of TYRO3 and GAS6, which could be prevented by neutralization of TLR5. Our results underscore the role of TLR dysregulations in AD, suggesting the presence of an immunosuppressive response during moderate disease stages, and implicate TAM signaling in AD immune dysregulation

DNA methylation links between depression and immunity

DNA methylation is a reversible epigenetic mechanism of transcriptional regulation. Changes in DNA methylation patterns are influenced by internal and external factors, and have been associated with various human diseases. We hypothesized that specific methylation changes occur in depressed individuals, and that these changes are associated with disease progression and responses to pharmacological treatments. To test our hypothesis, we analyzed DNA methylation-wide changes in the BiDirect Study's depression and control cohorts. Over the course of two consecutive follow-up visits in 3-year intervals from baseline (i.e. 3 and 6 years after initial assessment), we identified a set of changes in methylation sites within gene enhancer and promoter regions that consistently changed only in depression patients or only in control individuals, respectively. Longitudinal changes in these methylation sites correlated with changes in circulating markers of inflammation and were enriched in biological processes related to innate and adaptive immunity. Currently, we are starting to explore the translational value of these findings by investigating their relationships with depressive symptoms and immunity. Moreover, by applying different machine learning algorithms, we test the utility of a prioritized subset of the identified methylation sites to predict disease status, disease progression, chronic inflammation status and antidepressant response. Overall, we expect to leverage longitudinal DNA methylation information to gain insights into the role of immunity in depression and generate computational tools with potential applications in the clinic