Kelly R. Miller

Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline

The pathology of Alzheimers disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (Aβ). Using the APPPS1 Alzheimers disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aβ species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimers disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimers disease pathology and cognitive deficits.

Functional impairment of microglia coincides with beta-amyloid deposition in mice with Alzheimer-like pathology

Microglial cells closely interact with senile plaques in Alzheimer’s disease and acquire the morphological appearance of an activated phenotype. The significance of this microglial phenotype and the impact of microglia for disease progression have remained controversial. To uncover and characterize putative changes in the functionality of microglia during Alzheimer’s disease, we directly assessed microglial behavior in two mouse models of Alzheimer’s disease. Using in vivo two-photon microscopy and acute brain slice preparations, we found that important microglial functions - directed process motility and phagocytic activity - were strongly impaired in mice with Alzheimer’s disease-like pathology compared to age-matched non-transgenic animals. Notably, impairment of microglial function temporally and spatially correlated with Aβ plaque deposition, and phagocytic capacity of microglia could be restored by interventionally decreasing amyloid burden by Aβ vaccination. These data suggest that major microglial functions progressively decline in Alzheimer’s disease with the appearance of Aβ plaques, and that this functional impairment is reversible by lowering Aβ burden, e.g. by means of Aβ vaccination.

Microglia actions in Alzheimer’s disease.

The identification of microglia-associated, neurological disease-causing mutations in patients, combined with studies in mouse models has highlighted microglia, the brain’s intrinsic myeloid cells, as key modulators of pathogenesis and disease progression in neurodegenerative diseases. In Alzheimer’s disease (AD) in particular, the activation and accumulation of microglial cells around β-Amyloid (Aβ) plaques has long been described and is believed to result in chronic neuroinflammation—a term that, despite being commonly used, lacks a precise definition. This seemingly directed response of microglia to amyloid deposits conflicts with the fact that the increasing buildup of Aβ plaques is not inhibited by these cells during disease progression. While recent evidence suggests that microglia lose their intrinsic beneficial function during the course of AD and may even acquire a “toxic” phenotype over time, Aβ may also simply not be an appropriate trigger to induce phagocytosis and degradation by microglia in vivo. As recent experimental evidence has indicated the importance of the microglia in AD pathogenesis, future efforts aimed at tackling this disease via utilization or modulation of microglia or factors therefrom appear to be an exciting and challenging research front.

Essential role of interleukin-6 in post-stroke angiogenesis

Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6(-/-) mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6(-/-) mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6(-/-) mice. In addition, systemic neoangiogenesis was impaired in IL-6(-/-) mice. Transplantation of interleukin-6 competent bone marrow into IL-6(-/-) mice (IL-6(chi)) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6(chi) mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case, whereas oxygen-glucose deprivation did not. However, oxygen-glucose deprivation of organotypic brain slices resulted in strong upregulation of interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection.

Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease–like mice

Prokop et al. demonstrate that conditional ablation of resident microglia in a mouse model of Alzheimer’s disease (AD) results in no significant change in amyloid-β burden, despite nearly complete replacement with peripheral myeloid cells. The findings suggest that additional triggers appear to be required to exploit the full potential of myeloid cell–based therapies for AD.

Enlarging the nosological spectrum of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS)

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disease clinically characterized by cognitive decline, personality changes, motor impairment, parkinsonism and seizures. Recently, mutations in the colony‐stimulating factor‐1 receptor (CSF1R) gene have been shown to be associated with HDLS. We report clinical, neuropathological and molecular genetic findings of patients from a new family with a mutation in the CSF1R gene. Disease onset was earlier and disease progression was more rapid compared with previously reported patients. Psychiatric symptoms including personality changes, alcohol abuse and severe depression were the first symptoms in male patients. In the index, female patient, the initial symptom was cognitive decline. Magnetic resonance imaging (MRI) showed bilateral, confluent white matter lesions in the cerebrum. Stereotactic biopsy revealed loss of myelin and microglial activation as well as macrophage infiltration of the parenchyma. Numerous axonal swellings and spheroids were present. Ultrastructural analysis revealed pigment‐containing macrophages. Axonal swellings were detected by electron microscopy not only in the central nervous system (CNS) but also in skin nerves. We identified a heterozygous mutation (c.2330G>A, p.R777Q) in the CSF1R gene. Through this report, we aim to enlarge the nosological spectrum of HDLS, providing new clinical descriptions as well as novel neuropathological findings from the peripheral nervous system.

CNS myeloid cells critically regulate heat hyperalgesia

&NA; Activation of non‐neuronal microglia is thought to play a causal role in spinal processing of neuropathic pain. To specifically investigate microglia‐mediated effects in a model of neuropathic pain and overcome the methodological limitations of previous approaches exploring microglia function upon nerve injury, we selectively ablated resident microglia by intracerebroventricular ganciclovir infusion into male CD11b‐HSVTK‐transgenic mice, which was followed by a rapid, complete, and persistent (23 weeks) repopulation of the CNS by peripheral myeloid cells. In repopulated mice that underwent sciatic nerve injury, we observed a normal response to mechanical stimuli, but an absence of thermal hypersensitivity ipsilateral to the injured nerve. Furthermore, we found that neuronal expression of calcitonin gene‐related peptide (CGRP), which is a marker of neurons essential for heat responses, was diminished in the dorsal horn of the spinal cord in repopulated mice. These findings identify distinct mechanisms for heat and mechanical hypersensitivity and highlight a crucial contribution of CNS myeloid cells in the facilitation of noxious heat.

Local partial depletion of CD11b+ cells and their influence on choroidal neovascularization using the CD11b-HSVTK mouse model

To assess the influence of retinal macrophages and microglia on the formation of choroidal neovascularization (CNV). Therefore, we used a transgenic mouse (CD11b‐HSVTK) in which the application of ganciclovir (GCV) results in a depletion of CD11b+ cells.