Astrocyte Progenitors Derived From Patients With Alzheimer Disease Do Not Impair Stroke Recovery in Mice.

BACKGROUND: Species-specific differences in astrocytes and their Alzheimer disease-associated pathology may influence cellular responses to other insults. Herein, human glial chimeric mice were generated to evaluate how Alzheimer disease predisposing genetic background in human astrocytes contributes to behavioral outcome and brain pathology after cortical photothrombotic ischemia. METHODS: Neonatal (P0) immunodeficient mice of both sexes were transplanted with induced pluripotent stem cell-derived astrocyte progenitors from Alzheimer disease patients carrying PSEN1 exon 9 deletion (PSEN1 ΔE9), with isogenic controls, with cells from a healthy donor, or with mouse astrocytes or vehicle. After 14 months, a photothrombotic lesion was produced with Rose Bengal in the motor cortex. Behavior was assessed before ischemia and 1 and 4 weeks after the induction of stroke, followed by tissue perfusion for histology. RESULTS: Open field, cylinder, and grid-walking tests showed a persistent locomotor and sensorimotor impairment after ischemia and female mice had larger infarct sizes; yet, these were not affected by astrocytes with PSEN1 ΔE9 background. Staining for human nuclear antigen confirmed that human cells successfully engrafted throughout the mouse brain. However, only a small number of human cells were positive for astrocytic marker GFAP (glial fibrillary acidic protein), mostly located in the corpus callosum and retaining complex human-specific morphology with longer processes compared with host counterparts. While host astrocytes formed the glial scar, human astrocytes were scattered in small numbers close to the lesion boundary. Aß (beta-amyloid) deposits were not present in PSEN1 ΔE9 astrocyte-transplanted mice. CONCLUSIONS: Transplanted human cells survived and distributed widely in the host brain but had no impact on severity of ischemic damage after cortical photothrombosis in chimeric mice. Only a small number of transplanted human astrocytes acquired GFAP-positive glial phenotype or migrated toward the ischemic lesion forming glial scar. PSEN1 ΔE9 astrocytes did not impair behavioral recovery after experimental stroke.

Peripheral Administration of IL-13 Induces Anti-inflammatory Microglial/Macrophage Responses and Provides Neuroprotection in Ischemic Stroke.

Neuroinflammation is strongly induced by cerebral ischemia. The early phase after the onset of ischemic stroke is characterized by acute neuronal injury, microglial activation, and subsequent infiltration of blood-derived inflammatory cells, including macrophages. Therefore, modulation of the microglial/macrophage responses has increasingly gained interest as a potential therapeutic approach for the ischemic stroke. In our study, we investigated the effects of peripherally administered interleukin 13 (IL-13) in a mouse model of permanent middle cerebral artery occlusion (pMCAo). Systemic administration of IL-13 immediately after the ischemic insult significantly reduced the lesion volume, alleviated the infiltration of CD45+ leukocytes, and promoted the microglia/macrophage alternative activation within the ischemic region, as determined by arginase 1 (Arg1) immunoreactivity at 3 days post-ischemia (dpi). Moreover, IL-13 enhanced the expression of M2a alternative activation markers Arg1 and Ym1 in the peri-ischemic (PI) area, as well as increased plasma IL-6 and IL-10 levels at 3 dpi. Furthermore, IL-13 treatment ameliorated gait disturbances at day 7 and 14 and sensorimotor deficits at day 14 post-ischemia, as analyzed by the CatWalk gait analysis system and adhesive removal test, respectively. Finally, IL-13 treatment decreased neuronal cell death in a coculture model of neuroinflammation with RAW 264.7 macrophages. Taken together, delivery of IL-13 enhances microglial/macrophage anti-inflammatory responses in vivo and in vitro, decreases ischemia-induced brain cell death, and improves sensory and motor functions in the pMCAo mouse model of cerebral ischemia.

In-vivo detection of inflammation and neurodegeneration in the chronic phase after permanent embolic stroke in rats.

Neuroinflammation with microglia activation (MA) constitutes a key tissue response in acute stroke. Until now, its course in the chronic stage is less well defined. Here, we investigated (i) neuroinflammation in the chronic stage of a rat model of embolic stroke (n=6), and (ii) whether this process can be visualized in vivo by multimodal imaging using Magnetic Resonance Imaging (MRI) and Positron-Emission-Tomography (PET). Imaging data were verified using histology and immunohistochemistry. Repetitive PET studies until week 6 after stroke reveal poststroke inflammation as a dynamic process that involved the infarct, the surrounding tissue and secondary degenerating areas in a complex fashion. At the end, 7 months after stroke, neuroinflammation had almost completely vanished at the lesion side. In contrast, remote from the primarily infarcted areas, a marked T2(*)- hypointensity was detected in the ipsilateral thalamus. In the corresponding area, [(11)C]PK11195-PET detected microglia activation. Immunohistochemistry confirmed activated microglia in the ipsilateral thalamus with signs of extensive phagocytosis and iron deposition around plaque-like amyloid deposition. Neuronal staining (NeuN) revealed pronounced neuronal loss as an endpoint of neurodegeneration in these areas. In conclusion, the data demonstrate not only ongoing thalamic neuroinflammation but also marked neurodegeneration remote from the lesion site in the chronic phase after stroke in rats. Both, neuroinflammation and neurodegeneration were accessible to (immuno-) histochemical methods as well as to in vivo methods using [(11)C]PK11195-PET and T2(*)-weighted MRI. Although the functional roles of these dynamic processes remain to be elucidated, ongoing destruction of neuronal tissue is conceivable. Its inhibition using anti-inflammatory substances may be beneficial in chronic post-stroke conditions, while multimodal imaging can be used to evaluate putative therapeutic effects in vivo.