Osteopetrotic (op/op) mice have reduced microglia, no Aβ deposition, and no changes in dopaminergic neurons

<p>Abstract</p> <p>Background</p> <p>Activation of microglia is a part of the inflammatory response in neurodegenerative diseases but its role in the pathophysiology of these diseases is still unclear. The osteopetrotic (op/op) mouse lacks colony-stimulating factor-1 (CSF-1) and thus has a deficiency in microglia and macrophages. Prior reports have demonstrated that op/op mice deposit amyloid β (Aβ) plaques, similar to those found in Alzheimer's disease. The purpose of these studies was to confirm this and to determine if the lack of CSF-1 affects the development of dopaminergic neurons and the expression of CD200, a known microglial inhibitory protein.</p> <p>Method</p> <p>We examined the central nervous system of op/op mice at 30 days, 60 days and 7 months of age and wildtype littermates at 30 days using immunohistochemistry and histochemistry.</p> <p>Results</p> <p>We found a decrease in the number of microglia in 1 month-old op/op mice compared to wildtype (WT) littermates as measured by CD11b, CD45, CD32/16, CD68, CD204 and F4/80 immunoreactivity. Aβ plaques were not detected, while the number of dopaminergic neurons appeared normal. The expression of CD200 appeared to be normal, but there appeared to be a lower expression in the substantia nigra.</p> <p>Conclusion</p> <p>In contrast to a prior report we did not detect Aβ deposition in the central nervous system of op/op mice at 30 days, 60 days or 7 months of age and there was a normal number of dopaminergic neurons. This indicates that op/op mice may be useful to examine the effects of microglia on neurodegenerative disease progression by breeding them to different transgenic mouse models. In addition, the lack of CSF-1 does not appear to affect CD200 expression by neurons but we did note a decrease in the substantia nigra of op/op and WT mice, suggesting that this may be a mechanism by which microglia control may be attenuated in this specific area during Parkinson's disease.</p

Boosting with intranasal dendrimeric Aβ1–15 but not Aβ1–15 peptide leads to an effective immune response following a single injection of Aβ1–40/42 in APP-tg mice

BACKGROUND: Immunotherapy for Alzheimer's disease (AD) is emerging as a potential treatment. However, a clinical trial (AN1792) was halted after adverse effects occurred in a small subset of subjects, which may have been caused by a T cell-mediated immunological response. In general, aging limits the humoral immune response, therefore, immunogens and vaccination regimes are required that induce a strong antibody response with less potential for an adverse immune response. METHOD: In the current study, we immunized both wildtype and J20 APP-tg mice with a priming injection of Aβ1–40/42, followed by multiple intranasal boosts with the novel immunogen dAβ1–15 (16 copies of Aβ1–15 on a lysine tree), Aβ1–15 peptide or Aβ1–40/42 full length peptide. RESULTS: J20 APP-tg mice primed with Aβ1–40/42 subcutaneously and subsequently boosted intranasally with Aβ1–15 peptide did not generate a cellular or humoral immune response. In contrast, J20 APP-tg mice boosted intranasally with dAβ1–15 or full length Aβ1–40/42 produced high levels of anti-Aβ antibodies. Splenocyte proliferation was minimal in mice immunized with dAβ1–15. Wildtype littermates of the J20 APP-tg mice produced higher amounts of anti-Aβ antibodies compared to APP-tg mice but also had low T cell proliferation. The anti-Aβ antibodies were mainly composed of IgG2b and directed to an epitope within the Aβ1–7 region, regardless of the immunogen. Examination of the brain showed a significant reduction in Aβ plaque burden in the J20 APP-tg mice producing antibodies compared to controls. Biochemically, Aβ40 or Aβ42 were also reduced in brain homogenates and elevated in plasma but the changes did not reach significance. CONCLUSION: Our results demonstrate that priming with full length Aβ40/42 followed by boosting with dAβ1–15 but not Aβ1–15 peptide led to a robust humoral immune response with a minimal T cell response in J20 APP-tg mice. In addition, Aβ plaque burden was reduced in mice producing anti-Aβ antibodies. Interestingly, wildtype mice produced higher levels of anti-Aβ antibodies, indicating that immune tolerance may be present in J20 APP-tg mice. Together, these data suggest that dAβ1–15 but not Aβ1–15 peptide may be useful as a boosting immunogen in an AD vaccination regime

Angiogenesis is present in experimental autoimmune encephalomyelitis and pro-angiogenic factors are increased in multiple sclerosis lesions

<p>Abstract</p> <p>Background</p> <p>Angiogenesis is a common finding in chronic inflammatory diseases; however, its role in multiple sclerosis (MS) is unclear. Central nervous system lesions from both MS and experimental autoimmune encephalomyelitis (EAE), the animal model of MS, contain T cells, macrophages and activated glia, which can produce pro-angiogenic factors. Previous EAE studies have demonstrated an increase in blood vessels, but differences between the different phases of disease have not been reported. Therefore we examined angiogenic promoting factors in MS and EAE lesions to determine if there were changes in blood vessel density at different stages of EAE.</p> <p>Methods</p> <p>In this series of experiments we used a combination of vascular casting, VEGF ELISA and immunohistochemistry to examine angiogenesis in experimental autoimmune encephalomyelitis (EAE). Using immunohistochemistry we also examined chronic active MS lesions for angiogenic factors.</p> <p>Results</p> <p>Vascular casting and histological examination of the spinal cord and brain of rats with EAE demonstrated that the density of patent blood vessels increased in the lumbar spinal cord during the relapse phase of the disease (p < 0.05). We found an increased expression of VEGF by inflammatory cells and a decrease in the recently described angiogenesis inhibitor meteorin. Examination of chronic active human MS tissues demonstrated glial expression of VEGF and glial and blood vessel expression of the pro-angiogenic receptor VEGFR2. There was a decreased expression of VEGFR1 in the lesions compared to normal white matter.</p> <p>Conclusions</p> <p>These findings reveal that angiogenesis is intimately involved in the progression of EAE and may have a role in MS.</p

Basic Cyber Hygiene:Does It Work?

A number of security certifications for small- and medium-size enterprises have been proposed, but how effective are these schemes? We evaluated the effectiveness of Cyber Essentials and found that its security controls work well to mitigate threats that exploit vulnerabilities remotely with commodity-level tools

A Potent and Selective S1P1 Antagonist with Efficacy in Experimental Autoimmune Encephalomyelitis

SummaryLymphocyte trafficking is critically regulated by the Sphingosine 1-phosphate receptor-1 (S1P1), a G protein-coupled receptor that has been highlighted as a promising therapeutic target in autoimmunity. Fingolimod (FTY720, Gilenya) is a S1P1 receptor agonist that has recently been approved for the treatment of multiple sclerosis (MS). Here, we report the discovery of NIBR-0213, a potent and selective S1P1 antagonist that induces long-lasting reduction of peripheral blood lymphocyte counts after oral dosing. NIBR-0213 showed comparable therapeutic efficacy to fingolimod in experimental autoimmune encephalomyelitis (EAE), a model of human MS. These data provide convincing evidence that S1P1 antagonists are effective in EAE. In addition, the profile of NIBR-0213 makes it an attractive candidate to further study the consequences of S1P1 receptor antagonism and to differentiate the effects from those of S1P1 agonists

A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas

Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas

The differential migration of blood and lymph lymphocytes

grantor: University of TorontoIn sheep, a pool of lymphocytes resides in the blood that does not recirculate as efficiently as lymph lymphocytes. However, there is limited information on the differential migration of blood and lymph lymphocytes into nonlymphoid tissues or during inflammation. Therefore, experiments in this thesis were designed to investigate the migration of blood and lymph lymphocytes after splenectomy, antigen challenge to a single lymph node, into normal cerebral spinal fluid (CSF), and after TNF-Ã induced inflammation. Following neonatal splenectomy, no difference in the number or phenotype of lymphocytes was observed. However, splenectomy did result in an increased migration of lymph lymphocytes into lymph nodes and a trend towards a longer residence time in blood for the blood pool of lymphocytes. While splenectomy has little effect on the development or distribution of lymphocyte subsets in blood and lymph, evidence was obtained that it affects the rate of lymphocyte recirculation. Lymph node shutdown was induced by PPD in a BCG immunised sheep. Both lymph and blood pool CD4 lymphocytes increased in efferent lymph during lymph node shutdown. IFN-ã and IL-6 levels were increased in efferent lymph plasma during lymph node shutdown and may have a role in both the recruitment and retention of lymphocytes. Lymph lymphocytes preferentially migrate into CSF and afferent lymph under normal conditions, implying that lymph lymphocytes have a greater role in immune surveillance as compared to blood lymphocytes. After the intracerebroventricular infusion of TNF-Ã, blood lymphocytes are found in a greater percentage as compared to lymph lymphocytes. In both CSF and the perivascular spaces of the brain, an inflammatory infiltrate composed of CD4, CD8 and ã[delta] lymphocytes was observed. Together these data demonstrate that under inflammatory conditions and following splenectomy there are differences in the migration of blood and lymph lymphocytes. The results in this thesis provide some basic data into the migration of the blood and lymph pools of lymphocytes and provides the background for further investigations into the migration and functional differences between blood and lymph lymphocytes.Ph.D