Bradykinin promotes immune responses in differentiated embryonic neurospheres carrying APPswe and PS1dE9 mutations.

BACKGROUND: Neural progenitor cells (NPCs) can be cultivated from developing brains, reproducing many of the processes that occur during neural development. They can be isolated from a variety of animal models, such as transgenic mice carrying mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN 1 and 2), characteristic of familial Alzheimer's disease (fAD). Modulating the development of these cells with inflammation-related peptides, such as bradykinin (BK) and its antagonist HOE-140, enables the understanding of the impact of such molecules in a relevant AD model. RESULTS: We performed a global gene expression analysis on transgenic neurospheres treated with BK and HOE-140. To validate the microarray data, quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) was performed on 8 important genes related to the immune response in AD such as CCL12, CCL5, CCL3, C3, CX3CR1, TLR2 and TNF alpha and Iba-1. Furthermore, comparative analysis of the transcriptional profiles was performed between treatments, including gene ontology and reactome enrichment, construction and analysis of protein-protein interaction networks and, finally, comparison of our data with human dataset from AD patients. The treatments affected the expression levels of genes mainly related to microglia-mediated neuroinflammatory responses, with BK promoting an increase in the expression of genes that enrich processes, biological pathways, and cellular components related to immune dysfunction, neurodegeneration and cell cycle. B2 receptor inhibition by HOE-140 resulted in the reduction of AD-related anomalies caused in this system. CONCLUSIONS: BK is an important immunomodulatory agent and enhances the immunological changes identified in transgenic neurospheres carrying the genetic load of AD. Bradykinin treatments modulate the expression rates of genes related to microglia-mediated neuroinflammation. Inhibiting bradykinin activity in Alzheimer's disease may slow disease progression.

Differentiated Embryonic Neurospheres from Familial Alzheimer's Disease Model Show Innate Immune and Glial Cell Responses.

Proteins involved in the Alzheimer's disease (AD), such as amyloid precursor protein (APP) and presenilin-1 (PS1), play critical roles in early development of the central nervous system (CNS), as well as in innate immune and glial cell responses. Familial AD is associated with the presence of APPswe and PS1dE9 mutations. However, it is still unknown whether these mutations cause deficits in CNS development of carriers. We studied genome-wide gene expression profiles of differentiated neural progenitor cells (NPCs) from wild-type and APPswe/PS1dE9 mouse embryo telencephalon. The occurrence of strong innate immune and glial cell responses in APPswe/PS1dE9 neurospheres mainly involves microglial activation, inflammatory mediators and chemokines. APPswe/PS1dE9 neurospheres augmented up to 100-fold CCL12, CCL5, CCL3, C3, CX3CR1, TLR2 and TNF-alpha expression levels, when compared to WT neurospheres. Expression levels of the glia cell marker GFAP and microglia marker Iba-1 were up to 20-fold upregulated in APPswe/PS1dE9 neurospheres. The secretome of differentiated APPswe/PS1dE9 NPCs revealed enhanced chemoattraction of peripheral blood mononuclear cells. When evaluating the inferred protein interaction networks constructed from the array data, an improvement in astrocyte differentiation in APPswe/PS1dE9 neurospheres was evident in view of increased GFAP expression. Transgenic NPCs differentiated into neural phenotypes presented expression patterns of cytokine, glial cells, and inflammatory mediators characteristic of APPswe/PS1dE9 adult animals. Consequently, the neurogenic niche obtained from differentiation of embryonic APPswe/PS1dE9 neurospheres spontaneously presents several alterations observed in adult AD brains. Finally, our data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for familial AD.

Avaliação do percentual de compatibilidade HLA entre membros da mesma família para pacientes à espera de transplante de medula óssea em Santa Catarina, Brasil / Evaluation of the percentage of HLA compatibility between members of the same family for patients awaiting bone marrow transplantation in the state of Santa Catarina, Brazil

O transplante de medula óssea (TMO) é uma terapia especial utilizada para tratarpacientes com doenças hematológicas e certas alterações genéticas. Para que umtransplante seja bem sucedido, é necessário, entre outros fatores, que haja compatibilidade para moléculas codificadas pelos genes HLA. Em geral, os transplantes de melhor prognóstico são aqueles realizados entre irmãos HLA idênticos. Este trabalho tem por objetivo avaliar o percentual de compatibilidade de doadores de medula óssea (MO) nas famílias de pacientes que necessitam de TMO no estado de Santa Catarina. A coleta dos dados foi realizada no arquivo do Laboratório de Imunogenética do Hemocentro de Santa Catarina (Hemosc), compreendendo o período de 2000 a 2007. Foram totalizados 469 casos de pacientes à espera de TMO. Para estes, foram triados 2.463 possíveis doadores aparentados. Destes, 49,8% eram irmãos dos pacientes. Houve compatibilidade com algum membro da família do paciente em 213 (45,4%)casos, sendo que 99% das compatibilidades foram estabelecidas entre irmãos, 0,7% com mães e 0,3% com tios dos pacientes. Avaliando-se os doadores, obteve-se um total de 1.230 irmãos tipificados para doação, dos quais 296 (24,06%) apresentaram compatibilidade com o paciente para o qual realizaram a tipificação. Os dados encontrados neste estudo mostram que a possibilidade de que seja encontrado um doador compatível para TMO dentro da família do paciente, em Santa Catarina, é bastante promissora, principalmente entre irmãos do paciente.

Bone marrow transplantation (BMT) is a special therapy used to treat patients with hematological diseases and certain genetic disorders. For a transplant to be successful, it is necessary, among others factors, to have compatibility of the molecules coded by HLA genes. In general, the best prognosis for BMT is obtained with HLAidentical siblings. The aim of this work was to evaluate the percentage of compatibility between patients and possible related bone marrow donors in the state of Santa Catarina, Brazil. The data were collectedfrom the records of patient treated between 2000 and 2007 in the Immunogenetic Laboratory of the Hematology Centre of Santa Catarina (Hemosc). A total of 469 cases of patients waiting for BMT were identified. For these, 2463 possible related donors were screened with 49.8% being siblings of the patients. There was compatibility with a member of the patient's family in 213 (45.4%) cases: 99% of the compatibility was established with siblings, 0.7% with the mother and 0.3% with an uncle. Evaluating the donors, a total of 1230 siblings were screened for donation of which 296 (24.06%) presented compatibility with the patient for whom HLA typing had been carried out. These data show that the possibility of finding a compatible donor in the patient's family, in the State of Santa Catarina, is somewhat promising, especially among siblings.