Anna Nemirovsky

IFN-γ enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer’s disease

The generation of new neurons and glia from a precursor stem cell appears to take place in the adult brain. However, new neurons generated in the dentate gyrus decline sharply with age and to an even greater extent in neurodegenerative diseases. Here we raise the question whether peripheral immune mechanisms can generate immunity to such deficits in neuronal repair. We demonstrate that in contrast to primarily innate immunity cytokines, such as interleukin‐6 and tumor necrosis factor‐α, the adaptive immunity cytokine IFN‐γ enhances neurogenesis in the dentate gyrus of adult mice and improves the spatial learning and memory performance of the animals. In older mice, the effect of IFN‐γ is more pronounced in both wild‐type mice and mice with Alzheimers‐like disease and is associated with neuroprotection. In addition, IFN‐γ reverses the increase in oligodendrogenesis observed in a mouse model of Alzheimers disease. We demonstrate that limited amounts of IFN‐γ in the brain shape the neuropoietic milieu to enhance neurogenesis, possibly representing the normal function of the immune system in controlling brain inflammation and repair.—Baron, R., Nemirovsky, A., Harpaz, I., Cohen, H., Owens, T., Monsonego, A. IFN‐γ enhances neurogenesis in wild‐type mice and in a mouse model of Alzheimers disease. FASEB J. 22, 2843–2852 (2008)

T cells specifically targeted to amyloid plaques enhance plaque clearance in a mouse model of Alzheimer's disease.

Patients with Alzheimers disease (AD) exhibit substantial accumulation of amyloid-β (Aβ) plaques in the brain. Here, we examine whether Aβ vaccination can facilitate the migration of T lymphocytes to specifically target Aβ plaques and consequently enhance their removal. Using a new mouse model of AD, we show that immunization with Aβ, but not with the encephalitogenic proteolipid protein (PLP), results in the accumulation of T cells at Aβ plaques in the brain. Although both Aβ-reactive and PLP-reactive T cells have a similar phenotype of Th1 cells secreting primarily IFN-γ, the encephalitogenic T cells penetrated the spinal cord and caused experimental autoimmune encephalomyelitis (EAE), whereas Aβ T cells accumulated primarily at Aβ plaques in the brain but not the spinal cord and induced almost complete clearance of Aβ. Furthermore, while a single vaccination with Aβ resulted in upregulation of the phagocytic markers triggering receptors expressed on myeloid cells-2 (TREM2) and signal regulatory protein-β1 (SIRPβ1) in the brain, it caused downregulation of the proinflammatory cytokines TNF-α and IL-6. We thus suggest that Aβ deposits in the hippocampus area prioritize the targeting of Aβ-reactive but not PLP-reactive T cells upon vaccination. The stimulation of Aβ-reactive T cells at sites of Aβ plaques resulted in IFN-γ-induced chemotaxis of leukocytes and therapeutic clearance of Aβ.

Accelerated microglial pathology is associated with Aβ plaques in mouse models of Alzheimer's disease.

Microglia integrate within the neural tissue with a distinct ramified morphology through which they scan the surrounding neuronal network. Here, we used a digital tool for the quantitative morphometric characterization of fine cortical microglial structures in mice, and the changes they undergo with aging and in Alzheimers‐like disease. We show that, compared with microglia in young mice, microglia in old mice are less ramified and possess fewer branches and fine processes along with a slightly increased proinflammatory cytokine expression. A similar microglial pathology appeared 6–12 months earlier in mouse models of Alzheimers disease (AD), along with a significant increase in brain parenchyma lacking coverage by microglial processes. We further demonstrate that microglia near amyloid plaques acquire unique activated phenotypes with impaired process complexity. We thus show that along with a chronic proinflammatory reaction in the brain, aging causes a significant reduction in the capacity of microglia to scan their environment. This type of pathology is markedly accelerated in mouse models of AD, resulting in a severe microglial process deficiency, and possibly contributing to enhanced cognitive decline.

HLA-DR Alleles in Amyloid β-Peptide Autoimmunity: A Highly Immunogenic Role for the DRB1*1501 Allele

Active amyloid β-peptide (Aβ) immunization of patients with Alzheimer’s disease (AD) caused meningoencephalitis in ∼6% of immunized patients in a clinical trial. In addition, long-term studies of AD patients show varying degrees of Aβ Ab responses, which correlate with the extent of Aβ clearance from the brain. In this study, we examined the contribution of various HLA-DR alleles to these immune-response variations by assessing Aβ T cell reactivity, epitope specificity, and immunogenicity. Analysis of blood samples from 133 individuals disclosed that the abundant DR haplotypes DR15 (found in 36% of subjects), DR3 (in 18%), DR4 (12.5%), DR1 (11%), and DR13 (8%) were associated with Aβ-specific T cell responses elicited via distinct T cell epitopes within residues 15–42 of Aβ. Because the HLA-DRB1*1501 occurred most frequently, we examined the effect of Aβ challenge in humanized mice bearing this allele. The observed T cell response was remarkably strong, dominated by secretion of IFN-γ and IL-17, and specific to the same T cell epitope as that observed in the HLA-DR15-bearing humans. Furthermore, following long-term therapeutic immunization of an AD mouse model bearing the DRB1*1501 allele, Aβ was effectively cleared from the brain parenchyma and brain microglial activation was reduced. The present study thus characterizes HLA-DR alleles directly associated with specific Aβ T cell epitopes and demonstrates the highly immunogenic properties of the abundant allele DRB1*1501 in a mouse model of AD. This new knowledge enables us to explore the basis for understanding the variations in naturally occurring Aβ-reactive T cells and Aβ immunogenicity among humans.

Soil nitrifying enrichments as biofilter starters in intensive recirculating saline water aquaculture

Abstract Intensive recirculating aquaculture relies on biofilters to sustain satisfactory water quality in the ponds. Establishment of new biofilters in aquaculture ponds without a start-up culture requires a long period of time and may therefore cause significant losses and environmental harm due to discharge of nitrogen-rich effluents. A laboratory scale setup (7-l aquaria with shrimp and fish) demonstrated that an external start-up nitrifying enrichment culture performed similarly to the natural bacterial population of an established pond biofilter, and superior to the performance of similar biofilters without a start-up culture (control). Ammonia concentration in the control treatment increased daily and reached 18 mg l −1 during a 14-day experiment, whereas in the treated aquaria, it averaged less than 2 mg l −1 . Fish growth and survival were similar in the treated aquaria (average growth of 0.45 g/14 days, and 95% survival) and significantly higher than in the control (average growth of 0.0 g/14 days, and 80% survival). The source for the enrichment cultures was soil samples collected from the region where the farm is situated. This approach may lead to the development of bacterial amendments (probiotic products) that can be used as start-up cultures for new operations or damaged filters, and potentially enhance nitrification in established filters. As the cultures are collected from soils, it is unlikely that they will be contaminated with fish disease-causing agents. This will improve water quality and consequently aquatic animal production.

CD4 T cells in immunity and immunotherapy of Alzheimer's disease

Alzheimers disease (AD) is the most common form of dementia, with prevalence progressively increasing with aging. Pathological hallmarks of the disease include accumulation of amyloid β‐protein (Aβ) peptides and neurofibrillary tangles in the brain associated with glial activation and synaptotoxicity. In addition, AD involves peripheral and brain endogenous inflammatory processes that appear to enhance disease progression. More than a decade ago a new therapeutic paradigm emerged for AD, namely the activation of the adaptive immune system directly against the self‐peptide Aβ, aimed at lowering its accumulation in the brain. This was the first time that a brain peptide was used to vaccinate human subjects in a manner similar to classic viral or bacterial vaccines. The vaccination approach has taken several forms, from initially active to passive and then back to modified active vaccines. As the first two approaches to date failed to show sufficient efficacy, the last is presently being evaluated in ongoing clinical trials. The present review summarizes the immunogenic characteristics of Aβ in humans and mice and discusses past, present and future Aβ‐based immunotherapeutic approaches for AD. We emphasize potential pathogenic and beneficial roles of CD4 T cells in light of the pathogenesis and the general decline in T‐cell responsiveness evident in the disease.

Chronic exposure to stress predisposes to higher autoimmune susceptibility in C57BL/6 mice: glucocorticoids as a double-edged sword.

Stress activates the hypothalamic‐pituitary‐adrenocortical axis to promote the release of corticosterone (CORT), which consequently suppresses pathogenic stimulation of the immune system. Paradoxically, however, stress often promotes autoimmunity through yet unknown mechanisms. Here we investigated how chronic variable stress (CVS), and the associated alterations in CORT levels, affect the susceptibility to experimental autoimmune encephalomyelitis (EAE) in female and male C57BL/6 mice. Under baseline (nonstressed) conditions, females exhibited substantially higher CORT levels and an attenuated EAE with less mortality than males. However, CVS induced a significantly worsened EAE in females, which was prevented if CORT signaling was blocked. In addition, females under CVS conditions showed a shift toward proinflammatory Th1/Th17 versus Th2 responses and a decreased proportion of CD4+CD25+ Treg cells. This demonstrates that whereas C57BL/6 female mice generally exhibit higher CORT levels and an attenuated form of EAE than males, they become less responsive to the immunosuppressive effects of CORT under chronic stress and thereby prone to a higher risk of destructive autoimmunity.

Th1 Polarization of T Cells Injected into the Cerebrospinal Fluid Induces Brain Immunosurveillance

Although CD4 T cells reside within the cerebrospinal fluid, it is yet unclear whether and how they enter the brain parenchyma and migrate to target specific Ags. We examined the ability of Th1, Th2, and Th17 CD4 T cells injected intracerebroventricularly to migrate from the lateral ventricles into the brain parenchyma in mice. We show that primarily Th1 cells cross the ependymal layer of the ventricle and migrate within the brain parenchyma by stimulating an IFN-γ–dependent dialogue with neural cells, which maintains the effector function of the T cells. When injected into a mouse model of Alzheimer’s disease, amyloid-β (Aβ)–specific Th1 cells target Aβ plaques, increase Aβ uptake, and promote neurogenesis with no evidence of pathogenic autoimmunity or neuronal loss. Overall, we provide a mechanistic insight to the migration of cerebrospinal fluid CD4 T cells into the brain parenchyma and highlight implications on brain immunity and repair.

Immunity and neuronal repair in the progression of Alzheimer's disease : A brief overview

Alzheimers disease (AD) is an age-related progressive neurodegenerative disorder characterized by memory loss and severe cognitive decline. The etiology of the disease has not been explored, although a significant body of evidence suggests that neuronal dysfunction is caused by hyperphosphorylation and intracellular accumulation of the Tau protein, extracellular accumulation of the amyloid beta-peptide (Abeta), and the associated chronic activation of glial cells. Clearance of toxic Abeta, apoptotic cells and debris from the brain together with induction of neuronal repair mechanisms may all take place partially throughout the progression of AD, but therapeutic approaches based on knowledge of these processes have been unsuccessfully developed. Here, we address the question of whether autoimmune mechanisms can be boosted to safely facilitate the above-mentioned clearance and neuronal repair in the AD brain. We have previously demonstrated that depending on genetic background, autoimmunity targeted to Abeta is already induced in elderly individuals and in patients with AD. We have shown in a mouse model of AD that given a preexisting proinflammatory milieu in the brain, immune cells can enter the brain tissue and participate in clearance of Abeta. Furthermore, the decline in cognitive functions and neurogenesis throughout the progression of AD may also be affected by autoimmune mechanisms operating in the periphery and in the brain. In light of the so-far unsuccessful anti-inflammatory approaches to treating AD, we suggest that boosting - rather than suppressing - the endogenous immune mechanisms induced in AD may enhance repair pathways in the brain, provided that this approach can be safely applied.

Amyloid beta-HSP60 peptide conjugate vaccine treats a mouse model of Alzheimer's disease.

Active vaccination with amyloid beta peptide (Aβ) to induce beneficial antibodies was found to be effective in mouse models of Alzheimers disease (AD), but human vaccination trials led to adverse effects, apparently caused by exuberant T-cell reactivity. Here, we sought to develop a safer active vaccine for AD with reduced T-cell activation. We treated a mouse model of AD carrying the HLA-DR DRB1*1501 allele, with the Aβ B-cell epitope (Aβ 1-15) conjugated to the self-HSP60 peptide p458. Immunization with the conjugate led to the induction of Aβ-specific antibodies associated with a significant reduction of cerebral amyloid burden and of the accompanying inflammatory response in the brain; only a mild T-cell response specific to the HSP peptide but not to the Aβ peptide was found. This type of vaccination, evoking a gradual increase in antibody titers accompanied by a mild T-cell response is likely due to the unique adjuvant and T-cell stimulating properties of the self-HSP peptide used in the conjugate and might provide a safer approach to effective AD vaccination.