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Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

AbstractBackgroundRecent findings have indicated the presence of a progenitor domain at the marginal zone/layer 1 of the cerebral cortex, and it has been suggested that these progenitors have neurogenic and gliogenic potential. However, their contribution to the histogenesis of the cortex remains poorly understood due to difficulties associated with genetically manipulating these unique cells in a population-specific manner.ResultsWe have adapted the electroporation technique to target pial surface cells for rapid genetic manipulation at postnatal day 2. In vivo data show that most of these cells proliferate and progressively differentiate into both neuronal and glial subtypes. Furthermore, these cells localize to the superficial layers of the optic tectum and cerebral cortex prior to migration away from the surface.ConclusionsWe provide a foundation upon which future studies can begin to elucidate the molecular controls governing neural progenitor fate, migration, differentiation, and contribution to cortical and tectal histogenesis. Furthermore, specific genetic targeting of such neural progenitor populations will likely be of future clinical interest.

Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder clinically characterized by cognitive decline involving loss of memory, reasoning and linguistic ability. The amyloid cascade hypothesis holds that mismetabolism and aggregation of neurotoxic amyloid-β (Aβ) peptides, which are deposited as amyloid plaques, are the central etiological events in AD. Recent evidence from AD mouse models suggests that blood-borne mononuclear phagocytes are capable of infiltrating the brain and restricting β-amyloid plaques, thereby limiting disease progression. These observations raise at least three key questions: (1) what is the cell of origin for macrophages in the AD brain, (2) do blood-borne macrophages impact the pathophysiology of AD and (3) could these enigmatic cells be therapeutically targeted to curb cerebral amyloidosis and thereby slow disease progression? This review begins with a historical perspective of peripheral mononuclear phagocytes in AD, and moves on to critically consider the controversy surrounding their identity as distinct from brain-resident microglia and their potential impact on AD pathology.

While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as “immune privilege,” it is now clear that immune responses do occur in the CNS—giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue.

Background: Macrophages and dendritic cells (DCs) play key roles in host defense against HSV-1 infection. Although macrophages and DCs can be infected by herpes simplex virus type 1 (HSV1), both cell types are resistant to HSV-1 replication. The aim of our study was to determine factor (s) that are involved in the resistance of DCs and macrophages to productive HSV-1 infection. Results: We report here that, in contrast to bone marrow-derived DCs and macrophages from wild type mice, DCs and macrophages isolated from signal transducers and activators of transcription-1 deficient (STAT1(-/-)) mice were susceptible to HSV-1 replication and the production of viral mRNAs and DNA. There were differences in expression of immediate early, early, and late gene transcripts between STAT1(+/+) and STAT1(-/)-infected APCs. Conclusion: These results suggest for the first time that the JAK-STAT1 pathway is involved in blocking replication of HSV-1 in DCs and macrophages.

Interleukin (IL)-17-producing T helper cells ([T.sub.H]17) are a recently identified [CD4.sup.+] T cell subset distinct from T helper type 1 ([T.sub.H]1) and T helper type 2 ([T.sub.H]2) cells (1). [T.sub.H]17 cells can drive antigenspecific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE) (2), the mouse model for multiple sclerosis. The factors that are needed for the generation of [T.sub.H]17 cells have been well characterized (3-6). However, where and how the immune system controls [T.sub.H]17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory [T.sub.H]17 cells can be redirected to and controlled in the small intestine. [T.sub.H]17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that [T.sub.H]17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory [T.sub.H]17 cells simultaneously acquire a regulatory phenotype with invitro and invivoimmune-suppressive properties (r[T.sub.H]17). These results identify mechanisms limiting [T.sub.H]17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of [T.sub.H]17 cells., [T.sub.H]17 cells have been associated with the pathogenesis of several chronic inflammatory disorders, including rheumatoid arthritis and multiple sclerosis (2,7). To study the cellular and molecular mechanisms that control pathogenicity [...]

One unresolved issue in immune tolerance is what prevents self-reactive T cells from activation. In this study, we used a transgenic mouse model of targeted functional inactivation of TGF-[beta]R signaling in CD11[c.sup.+] cells (CD11[c.sup.dnR] mice) and showed a direct impact on the development of experimental autoimmune encephalomyelitis (EAE). We found that MO[G.sub.35-55] immunization of CD11[c.sup.dnR] mice results in strong inflammation of CNS, high frequency of T cells in CNS, increased levels of T helper 1 ([T.sub.H]1) and [T.sub.H]17 cytokines in the periphery, and lack of remission from EAE. Once crossed with mice prone to autoimmunity, double-transgenic CD11[c.sup.dnR][Mog.sup.TCR] mice revealed a spontaneous EAE-like disease characterized by early infiltration of activated myelin- specific T cells into CNS, activation of microglial cells, inflammation of CNS, dysfunction of locomotion, and premature death. We constructed chimeric mice and demonstrated that inactivation of TGF-[beta]R signaling in dendritic cells (DCs) results in augmented EAE-associated T cell responses. Our data provide direct evidence that TGF-[beta] can control autoimmunity via actions on DCs. brain | CNS | spinal cord

Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-[beta] peptide (A[beta]) into [beta]-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity (1). Transforming growth factor-[beta]s (TGF-[beta]s) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury (2). We genetically interrupted TGF-[beta] and downstream Smad2/3 signaling (TGF-[beta]-Smad2/3) in innate immune cells by inducing expression of CD11c promoter-driven dominant-negative TGF-[beta] receptor type II in C57BU6 mice (CD11c-DNR) (3), crossed these mice with mice overexpressing mutant human amyloid precursor protein, the Tg2576 Alzheimer's disease mouse model (4), and evaluated Alzheimer's disease-like pathology. Aged double-transgenic mice showed complete mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular [beta]-amyloid deposits and A[beta] abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of A[beta]-containing peripheral macrophages around cerebral vessels and [beta]-amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-[beta]-activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein-activated Smadl/5/8 signaling and increased A[beta] phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGF-[beta] receptor. Taken together, our results suggest that blockade of TGF-[beta]-Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer's disease., Alzheimer's disease is characterized by deposition of the 40-42-amino-acid A[beta] peptide, which is proteolytically derived from amyloid precursor protein (APP), resulting in cerebral [beta]-amyloid plaques (1). Despite low-level, chronic activation [...]

The flavivirus West Nile virus (WNV) is an emerging pathogen that causes life-threatening encephalitis in susceptible individuals. We investigated the role of the proinflammatory cytokine macrophage migration inhibitory factor (MIF), [...]

Alzheimer's disease (AD) immunotherapy accomplished by vaccination with [beta]-amyloid (A[beta]) peptide has proved efficacious in AD mouse models. However, 'active' A[beta] vaccination strategies for the treatment of cerebral amyloidosis without concurrent induction of detrimental side effects are lacking. We have developed a transcutaneous (t.c.) A[beta] vaccination approach and evaluated efficacy and monitored for deleterious side effects, including meningoencephalitis and microhemorrhage, in WT mice and a transgenic mouse model of AD. We demonstrate that t.c. immunization of WT mice with aggregated A[[beta].sub.1]-42 plus the adjuvant cholera toxin (CT) results in high-titer A[beta] antibodies (mainly of the Ig G1 class) and A[[beta].sub.1]-42-specific splenocyte immune responses. Confocal microscopy of the t.c. immunization site revealed Langerhans cells in areas of the skin containing the A[[beta].sub.1]-42 immunogen, suggesting that these unique innate immune cells participate in A[[beta].sub.1]-42 antigen processing. To evaluate the efficacy of t.c. immunization in reducing cerebral amyloidosis, transgenic PSAPP (APPsw, PSEN1dE9) mice were immunized with aggregated A[[beta].sub.1]-42 peptide plus CT. Similar to WT mice, PSAPP mice showed high A[beta] antibody titers. Most importantly, t.c. immunization with A[[beta].sub.1]-42 plus CT resulted in significant decreases in cerebral A[[beta].sub.1]-40,42 levels coincident with increased circulating levels of A[[beta].sub.1]-40,42, suggesting brain-to-blood efflux of A[beta]. Reduction in cerebral amyloidosis was not associated with deleterious side effects, including brain T cell infiltration or cerebral microhemorrhage. Together, these data suggest that t.c. immunization constitutes an effective and potentially safe treatment strategy for AD. Alzheimer's disease | cytokine | Langerhans cells | vaccine

West Nile virus (WNV), a mosquito-borne single-stranded (ss)RNA flavivirus, causes human disease of variable severity. We investigated the involvement of Toll-like receptor (Tlr) 3, which recognizes viral double-stranded (ds)RNA, on WNV infection. Tlr3-deficient (Tlr3[sup.-/-]) mice were more resistant to lethal WNV infection and had impaired cytokine production and enhanced viral load in the periphery, whereas in the brain, viral load, inflammatory responses and neuropathology were reduced compared to wild-type mice. Peripheral WNV infection led to a breakdown of the blood-brain barrier and enhanced brain infection in wild-type but not in Tlr3[sup.-/-] mice, although both groups were equally susceptible upon intracerebroventricular administration of the virus. Tumor necrosis factor-[alpha] receptor 1 signaling is vital for blood-brain barrier compromise upon Tlr3 stimulation by dsRNA or WNV. Collectively, WNV infection leads to a Tlr3-dependent inflammatory response, which is involved in brain penetration of the virus and neuronal injury., Author(s): Tian Wang [1, 6]; Terrence Town [2, 3, 6]; Lena Alexopoulou [2, 5, 6]; John F Anderson [4]; Erol Fikrig (corresponding author) [1]; Richard A Flavell [2, 3] WNV, [...]