Cranial irradiation disrupts homeostatic microglial dynamic behavior.

Cranial irradiation causes cognitive deficits that are in part mediated by microglia, the resident immune cells of the brain. Microglia are highly reactive, exhibiting changes in shape and morphology depending on the function they are performing. Additionally, microglia processes make dynamic, physical contacts with different components of their environment to monitor the functional state of the brain and promote plasticity. Though evidence suggests radiation perturbs homeostatic microglia functions, it is unknown how cranial irradiation impacts the dynamic behavior of microglia over time. Here, we paired in vivo two-photon microscopy with a transgenic mouse model that labels cortical microglia to follow these cells and determine how they change over time in cranial irradiated mice and their control littermates. We show that a single dose of 10 Gy cranial irradiation disrupts homeostatic cortical microglia dynamics during a 1-month time course. We found a lasting loss of microglial cells following cranial irradiation, coupled with a modest dysregulation of microglial soma displacement at earlier timepoints. The homogeneous distribution of microglia was maintained, suggesting microglia rearrange themselves to account for cell loss and maintain territorial organization following cranial irradiation. Furthermore, we found cranial irradiation reduced microglia coverage of the parenchyma and their surveillance capacity, without overtly changing morphology. Our results demonstrate that a single dose of radiation can induce changes in microglial behavior and function that could influence neurological health. These results set the foundation for future work examining how cranial irradiation impacts complex cellular dynamics in the brain which could contribute to the manifestation of cognitive deficits.

Noradrenergic signaling controls Alzheimer's disease pathology via activation of microglial ß2 adrenergic receptors.

Norepinephrine (NE) is a potent anti-inflammatory agent in the brain. In Alzheimer's disease (AD), the loss of NE signaling heightens neuroinflammation and exacerbates amyloid pathology. NE inhibits surveillance activity of microglia, the brain's resident immune cells, via their ß2 adrenergic receptors (ß2ARs). Here, we investigate the role of microglial ß2AR signaling in AD pathology in the 5xFAD mouse model of AD. We found that loss of cortical NE projections preceded the degeneration of NE-producing neurons and that microglia in 5xFAD mice, especially those microglia that were associated with plaques, significantly downregulated ß2AR gene expression early in amyloid pathology. Importantly, dampening microglial ß2AR signaling worsened plaque load and the associated neuritic damage, while stimulating microglial ß2AR signaling attenuated amyloid pathology. Our results suggest that microglial ß2AR could be explored as a potential therapeutic target to modify AD pathology.

Radiotherapy for non-cancer diseases: benefits and long-term risks.

PURPOSE: The discovery of X-rays was followed by a variety of attempts to treat infectious diseases and various other non-cancer diseases with ionizing radiation, in addition to cancer. There has been a recent resurgence of interest in the use of such radiotherapy for non-cancer diseases. Non-cancer diseases for which use of radiotherapy has currently been proposed include refractory ventricular tachycardia, neurodegenerative diseases (e.g. Alzheimer's disease and dementia), and Coronavirus Disease 2019 (COVID-19) pneumonia, all with ongoing clinical studies that deliver radiation doses of 0.5-25 Gy in a single fraction or in multiple daily fractions. In addition to such non-cancer effects, historical indications predominantly used in some countries (e.g. Germany) include osteoarthritis and degenerative diseases of the bones and joints. This narrative review gives an overview of the biological rationale and ongoing preclinical and clinical studies for radiotherapy proposed for various non-cancer diseases, discusses the plausibility of the proposed biological rationale, and considers the long-term radiation risks of cancer and non-cancer diseases. CONCLUSIONS: A growing body of evidence has suggested that radiation represents a double-edged sword, not only for cancer, but also for non-cancer diseases. At present, clinical evidence has shown some beneficial effects of radiotherapy for ventricular tachycardia, but there is little or no such evidence of radiotherapy for other newly proposed non-cancer diseases (e.g. Alzheimer's disease, COVID-19 pneumonia). Patients with ventricular tachycardia and COVID-19 pneumonia have thus far been treated with radiotherapy when they are an urgent life threat with no efficient alternative treatment, but some survivors may encounter a paradoxical situation where patients were rescued by radiotherapy but then get harmed by radiotherapy. Further studies are needed to justify the clinical use of radiotherapy for non-cancer diseases, and optimize dose to diseased tissue while minimizing dose to healthy tissue.

Pharmacologic Manipulation of Complement Receptor 3 Prevents Dendritic Spine Loss and Cognitive Impairment After Acute Cranial Radiation.

PURPOSE: Cranial irradiation induces healthy tissue damage that can lead to neurocognitive complications, negatively affecting patient quality of life. One damage indicator associated with cognitive impairment is loss of neuronal spine density. We previously demonstrated that irradiation-mediated spine loss is microglial complement receptor 3 (CR3) and sex dependent. We hypothesized that these changes are associated with late-delayed cognitive deficits and amenable to pharmacologic intervention. METHODS AND MATERIALS: Our model of cranial irradiation (acute, 10 Gy gamma) used male and female CR3-wild type and CR3-deficient Thy-1 YFP mice of C57BL/6 background. Forty-five days after irradiation and behavioral testing, we quantified spine density and markers of microglial reactivity in the hippocampal dentate gyrus. In a separate experiment, male Thy-1 YFP C57BL/6 mice were treated with leukadherin-1, a modulator of CR3 function. RESULTS: We found that male mice demonstrate irradiation-mediated spine loss and cognitive deficits but that female and CR3 knockout mice do not. These changes were associated with greater reactivity of microglia in male mice. Pharmacologic manipulation of CR3 with LA1 prevented spine loss and cognitive deficits in irradiated male mice. CONCLUSIONS: This work improves our understanding of irradiation-mediated mechanisms and sex dependent responses and may help identify novel therapeutics to reduce irradiation-induced cognitive decline and improve patient quality of life.

Inconsistent Effects of Glatiramer Acetate Treatment in the 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that involves strong inflammatory components. Aberrant and prolonged inflammation in the CNS is thought to contribute to the development of the pathology. The use of single cytokine approaches to curb or leverage inflammatory mechanisms for disease modifying benefit has often resulted in conflicting data. Furthermore, these treatments were usually delivered locally into the CNS parenchyma, complicating translational efforts. To overcome these hurdles, we tested the use of glatiramer acetate (GA) in reducing amyloid beta (Aß) plaque pathology in the 5xFAD model of AD. GA immunizations were begun at the ages of 2.5 months, 5.5 months, and 8.5 months, and GA was delivered weekly for 8 weeks. While previous data describe potential benefits of GA immunization in decreasing Aß levels in murine models of AD, we found modest decreases in Aß levels if given during the development of pathology but, surprisingly, found increased Aß levels if GA was administered at later stages. The impact of GA treatment was only significant for female mice. Furthermore, we observed no changes between microglial uptake of plaque, CD11c immunopositivity of microglia, or levels of TMEM119 and P2Ry12 on microglia. Overall, these data warrant exercising caution when aiming to repurpose GA for AD.

High-Energy, Whole-Body Proton Irradiation Differentially Alters Long-Term Brain Pathology and Behavior Dependent on Sex and Alzheimer's Disease Mutations.

Whole-body exposure to high-energy particle radiation remains an unmitigated hazard to human health in space. Ongoing experiments at the NASA Space Radiation Laboratory and elsewhere repeatedly show persistent changes in brain function long after exposure to simulations of this unique radiation environment, although, as is also the case with proton radiotherapy sequelae, how this occurs and especially how it interacts with common comorbidities is not well-understood. Here, we report modest differential changes in behavior and brain pathology between male and female Alzheimer's-like and wildtype littermate mice 7-8 months after exposure to 0, 0.5, or 2 Gy of 1 GeV proton radiation. The mice were examined with a battery of behavior tests and assayed for amyloid beta pathology, synaptic markers, microbleeds, microglial reactivity, and plasma cytokines. In general, the Alzheimer's model mice were more prone than their wildtype littermates to radiation-induced behavior changes, and hippocampal staining for amyloid beta pathology and microglial activation in these mice revealed a dose-dependent reduction in males but not in females. In summary, radiation-induced, long-term changes in behavior and pathology, although modest, appear specific to both sex and the underlying disease state.

Radiation and CNS effects: summary of evidence from a recent symposium of the Radiation Research Society.

This article summarizes a Symposium on 'Radiation risks of the central nervous system' held virtually at the 67th Annual Meeting of the Radiation Research Society, 3-6 October 2021. Repeated low-dose radiation exposure over a certain period could lead to reduced neuronal proliferation, altered neurogenesis, neuroinflammation and various neurological complications, including psychological consequences, necessitating further research in these areas. Four speakers from radiation biology, genetics and epidemiology presented the latest data from their studies seeking insights into this important topic. This symposium highlighted new and important directions for further research on mental health disorders, neurodegenerative conditions and cognitive impairment. Future studies will examine risks of mental and behavioral disorders and neurodegenerative diseases following protracted radiation exposures to better understand risks of occupational exposures as well as provide insights into risks from exposures to galactic cosmic rays.

Repopulated microglia induce expression of Cxcl13 with differential changes in Tau phosphorylation but do not impact amyloid pathology.

BACKGROUND: Adult microglia rely on self-renewal through division to repopulate and sustain their numbers. However, with aging, microglia display morphological and transcriptional changes that reflect a heightened state of neuroinflammation. This state threatens aging neurons and other cells and can influence the progression of Alzheimer's disease (AD). In this study, we sought to determine whether renewing microglia through a forced partial depletion/repopulation method could attenuate AD pathology in the 3xTg and APP/PS1 mouse models. METHODS: We pharmacologically depleted the microglia of two cohorts of 21- to 22-month-old 3xTg mice and one cohort of 14-month-old APP/PS1 mice using PLX5622 formulated in chow for 2 weeks. Following depletion, we returned the mice to standard chow diet for 1 month to allow microglial repopulation. We assessed the effect of depletion and repopulation on AD pathology, microglial gene expression, and surface levels of homeostatic markers on microglia using immunohistochemistry, single-cell RNAseq and flow cytometry. RESULTS: Although we did not identify a significant impact of microglial repopulation on amyloid pathology in either of the AD models, we observed differential changes in phosphorylated-Tau epitopes after repopulation in the 3xTg mice. We provide evidence that repopulated microglia in the hippocampal formation exhibited changes in the levels of homeostatic microglial markers. Lastly, we identified novel subpopulations of microglia by performing single-cell RNAseq analysis on CD45int/+ cells from hippocampi of control and repopulated 3xTg mice. In particular, one subpopulation induced after repopulation is characterized by heightened expression of Cxcl13. CONCLUSION: Overall, we found that depleting and repopulating microglia causes overexpression of microglial Cxcl13 with disparate effects on Tau and amyloid pathologies.

Calcitonin gene-related peptide: An intra-articular therapeutic target for TMJ disorders.

OBJECTIVES: The goal of this project was to evaluate the role of calcitonin gene-related peptide (CGRP) in the development of arthritis. METHODS: Herein, we employed somatic mosaic analysis in two different joints by FIV(CGRP) intra-articular inoculation in the knees or temporomandibular joints (TMJ) of young adult male C57/BL6 mice. FIV(CGRP) is a feline immunodeficiency virus over-expressing full-length CGRP. Joint pathology and function were evaluated at the histopathological and behavioral levels. In addition, CGRP signaling was inhibited by intra-articular inoculation using FIV(CGRP8-37 ), such that the inhibitory peptide CGRP(8-37) was overexpressed 4 weeks after induction of joint inflammation in the TMJ of IL-1ßXAT transgenic mouse model. The mice were evaluated for behavior and killed for evaluation of knee and TMJ pathology. RESULTS: Overexpression of CGRP in the joints of wild-type mice induced the development of joint anomalies, including meniscal hypertrophy and articular pathology, associated with nocifensive behavior. Intriguingly, overexpression of the CGRP(8-37) inhibitory peptide in the knee and TMJ of IL-1ßXAT transgenic mice with joint inflammation resulted in partial amelioration of the attendant joint pathology. CONCLUSIONS: The results of this study suggest that CGRP is sufficient and necessary for the development of joint pathology and may serve as an intra-articular therapeutic target using gene therapy or monoclonal antibody-based therapies.

Gas6 induces inflammation and reduces plaque burden but worsens behavior in a sex-dependent manner in the APP/PS1 model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease is the leading cause of dementia worldwide. TAM receptor tyrosine kinases (Tyro3, Axl, MerTK) are known for their role in engagement of phagocytosis and modulation of inflammation, and recent evidence suggests a complex relationship between Axl, Mer, and microglial phagocytosis of amyloid plaques in AD. Gas6, the primary CNS TAM ligand, reduces neuroinflammation and improves outcomes in murine models of CNS disease. Therefore, we hypothesized that AAV-mediated overexpression of Gas6 would alleviate plaque pathology, reduce neuroinflammation, and improve behavior in the APP/PS1 model of Alzheimer's disease. METHODS: Adeno-associated viral vectors were used to overexpress Gas6 in the APP/PS1 model of Alzheimer's disease. Nine-month-old male and female APP/PS1 and nontransgenic littermates received bilateral stereotactic hippocampal injections of AAV-Gas6 or AAV-control, which expresses a non-functional Gas6 protein. One month after injections, mice underwent a battery of behavioral tasks to assess cognitive function and brains were processed for immunohistochemical and transcriptional analyses. RESULTS: Gas6 overexpression reduced plaque burden in male APP/PS1 mice. However, contrary to our hypothesis, Gas6 increased pro-inflammatory microglial gene expression and worsened contextual fear conditioning compared to control-treated mice. Gas6 overexpression appeared to have no effect on phagocytic mechanisms in vitro or in vivo as measured by CD68 immunohistochemistry, microglial methoxy-04 uptake, and primary microglial uptake of fluorescent fibrillar amyloid beta. CONCLUSION: Our data describes a triad of worsened behavior, reduced plaque number, and an increase in proinflammatory signaling in a sex-specific manner. While Gas6 has historically induced anti-inflammatory signatures in the peripheral nervous system, our data suggest an alternative, proinflammatory role in the context of Alzheimer's disease pathology.

Long-Term Sex- and Genotype-Specific Effects of 56Fe Irradiation on Wild-Type and APPswe/PS1dE9 Transgenic Mice.

Space radiation presents a substantial threat to travel beyond Earth. Relatively low doses of high-energy particle radiation cause physiological and behavioral impairments in rodents and may pose risks to human spaceflight. There is evidence that 56Fe irradiation, a significant component of space radiation, may be more harmful to males than to females and worsen Alzheimer's disease pathology in genetically vulnerable models. Yet, research on the long-term, sex- and genotype-specific effects of 56Fe irradiation is lacking. Here, we irradiated 4-month-old male and female, wild-type and Alzheimer's-like APP/PS1 mice with 0, 0.10, or 0.50 Gy of 56Fe ions (1GeV/u). Mice underwent microPET scans before and 7.5 months after irradiation, a battery of behavioral tests at 11 months of age and were sacrificed for pathological and biochemical analyses at 12 months of age. 56Fe irradiation worsened amyloid-beta (Aß) pathology, gliosis, neuroinflammation and spatial memory, but improved motor coordination, in male transgenic mice and worsened fear memory in wild-type males. Although sham-irradiated female APP/PS1 mice had more cerebral Aß and gliosis than sham-irradiated male transgenics, female mice of both genotypes were relatively spared from radiation effects 8 months later. These results provide evidence for sex-specific, long-term CNS effects of space radiation.

Evaluating Effects of Glatiramer Acetate Treatment on Amyloid Deposition and Tau Phosphorylation in the 3xTg Mouse Model of Alzheimer's Disease.

Neuroinflammation driven by the accumulation of amyloid ß (Aß) can lead to neurofibrillary tangle formation in Alzheimer's Disease (AD). To test the hypothesis that an anti-inflammatory immunomodulatory agent might have beneficial effects on amyloid and tau pathology, as well as microglial phenotype, we evaluated glatiramer acetate (GA), a multiple sclerosis drug thought to bias type 2 helper T (Th2) cell responses and alternatively activate myeloid cells. We administered weekly subcutaneous injections of GA or PBS to 15-month-old 3xTg AD mice, which develop both amyloid and tau pathology, for a period of 8 weeks. We found that subcutaneous administration of GA improved behavioral performance in novel object recognition and decreased Aß plaque in the 3xTg AD mice. Changes in tau phosphorylation were mixed with specific changes in phosphoepitopes seen in immunohistochemistry but not observed in western blot. In addition, we found that there was a trend toward increased microglia complexity in 3xTg mice treated with GA, suggesting a shift toward homeostasis. These findings correlated with subtle changes in the microglial transcriptome, in which the most striking difference was the upregulation of Dcstamp. Lastly, we found no evidence of changes in proportions of major helper T cell (Th) subtypes in the periphery. Overall, our study provides further evidence for the benefits of immunomodulatory therapies that alter the adaptive immune system with the goal of modifying microglia responses for the treatment of Alzheimer's Disease.

In Vivo Imaging of the Microglial Landscape After Whole Brain Radiation Therapy.

PURPOSE: Whole brain radiation therapy (WBRT) is an important treatment for patients with multiple brain metastases, but can also cause cognitive deterioration. Microglia, the resident immune cells of the brain, promote a proinflammatory environment and likely contribute to cognitive decline after WBRT. To investigate the temporal dynamics of the microglial reaction in individual mice to WBRT, we developed a novel in vivo experimental model using cranial window implants and longitudinal imaging. METHODS AND MATERIALS: Chronic cranial windows were surgically implanted over the somatosensory cortex of transgenic Cx3cr1-enhanced green fluorescent protein (EGFP)/+ C57BL/6 mice, where microglia were fluorescently tagged with EGFP. Cx3cr1-EGFP/+ mice were also crossed with Thy1-YFP mice to fluorescently dual label microglia and subsets of neurons throughout the brain. Three weeks after window implantation and recovery, computed tomography image guided WBRT was delivered (single dose 10 Gy using two 5 Gy parallel-opposed lateral beams). Radiation dosing was confirmed using radiochromic film. Then, in vivo 2-photon microscopy was used to longitudinally image the microglial landscape and microglial motility at 7 days and 16 days after irradiation in the same mice. RESULTS: Film dosimetry confirmed the average delivered dose per beam at midpoint was accurate within 2%, with no attenuation from the window frame. By 7 days after WBRT, significant changes in the microglial landscape were seen, characterized by apparent loss of microglial cells (20%) and significant rearrangements of microglial location with time after irradiation (36% of cells not found in original location). CONCLUSIONS: Using longitudinal in vivo 2-photon imaging, this study demonstrated the feasibility of imaging microglia-neuron interactions and defining how microglia react to WBRT in the same mouse. Having demonstrated utility of the model, this experimental paradigm can be used to investigate the dynamic changes of many different brain cell types and their interactions after WBRT and uncover the underlying cellular mechanisms of WBRT-induced cognitive decline.

Effects of concentrated ambient ultrafine particulate matter on hallmarks of Alzheimer's disease in the 3xTgAD mouse model.

BACKGROUND: Exposure to air pollution has been identified as a possible environmental contributor to Alzheimer's Disease (AD) risk. As the number of people with AD worldwide continues to rise, it becomes vital to understand the nature of this potential gene-environment interaction. This study assessed the effects of short-term exposures to concentrated ambient ultrafine particulates (UFP, <100 nm) on measurements of amyloid-ß, tau, and microglial morphology. METHODS: Two cohorts of aged (12.5-14 months) 3xTgAD and NTg mice were exposed to concentrated ambient UFP or filtered air for 2 weeks (4-h/day, 4 days/week). Bronchoalveolar lavage fluid and brain tissue were collected twenty-four hours following the last exposure to evaluate lung inflammation, tau pathology, amyloid-ß pathology, and glial cell morphology. RESULTS: No exposure- or genotype-related changes were found with any of the measures of lung inflammation or in the hippocampal staining density of astrocyte marker glial fibrillary acidic protein. The microglia marker, ionized calcium binding adaptor molecule 1, and amyloid-ß marker, 6E10, exhibited significant genotype by exposure interactions such that levels were lower in the UFP-exposed as compared to filtered air-exposed 3xTgAD mice. When microglia morphology was assessed by Sholl analysis, microglia from both NTg mouse groups were ramified. The 3xTgAD air-exposed mice had the most ameboid microglia, while the 3xTgAD UFP-exposed mice had microglia that were comparatively more ramified. The 3xTgAD air-exposed mice had more plaques per region of interest as measured by Congo red staining as well as more plaque-associated microglia than the 3xTgAD UFP-exposed mice. The number of non-plaque-associated microglia was not affected by genotype or exposure. Levels of soluble and insoluble human amyloid-ß42 protein were measured in both 3xTgAD groups and no exposure effect was found. In contrast, UFP-exposure led to significant elevations in phosphorylated tau in 3xTgAD mice as compared to those that were exposed to air, as measured by pT205 staining. CONCLUSIONS: Exposure to environmentally relevant levels of ultrafine particulates led to changes in tau phosphorylation and microglial morphology in the absence of overt lung inflammation. Such changes highlight the need to develop greater mechanistic understanding of the link between air pollution exposure and Alzheimer's disease.

Retrospective analysis of the hemodynamic consequences of prehospital supplemental oxygen in acute stroke.

OBJECTIVE: Hyperoxia, the delivery of high levels of supplemental oxygen (sO2) despite normoxia, may increase cerebral oxygenation to penumbral tissue and improve stroke outcomes. However, it may also alter peripheral hemodynamic profiles with potential negative effects on cerebral blood flow (CBF). This study examines the hemodynamic consequences of prehospital sO2 in stroke. METHODS: A retrospective analysis of adult acute stroke patients (aged ≥18 years) presenting via EMS to an academic Comprehensive Stroke Center between January 1, 2013 and December 31, 2017 was conducted using demographic and clinical characteristics obtained from Get with the Guidelines-Stroke registry and subjects' medical records. Outcomes were compared across three groups based on prehospital oxygen saturation and sO2 administration. Chi-square, ANOVA, and multivariable linear regression were used to determine if sO2 was associated with differences in peripheral hemodynamic profiles. RESULTS: All subjects had similar initial EMS vitals except for oxygen saturation. However, both univariate and multivariable analysis revealed that hyperoxia subjects had slightly lower average ED mean arterial pressures (MAP) compared to normoxia (Cohen's d = 0.313). CONCLUSIONS: Prehospital-initiated hyperoxia for acute stroke is associated with a small, but significant decrease in average ED MAP, without changes in heart rate, compared to normoxia. While limited by the inability to link changes in peripheral hemodynamical profiles directly to changes in CBF, this study suggests that hyperoxia may result in a relative hypotension. Further studies are needed to determine if this small change in peripheral vascular resistance translates into a clinically significant reduced CBF.

Cognitively supernormal older adults maintain a unique structural connectome that is resistant to Alzheimer's pathology.

Studying older adults with excellent cognitive capacities (Supernormals) provides a unique opportunity for identifying factors related to cognitive success - a critical topic across lifespan. There is a limited understanding of Supernormals' neural substrates, especially whether any of them attends shaping and supporting superior cognitive function or confer resistance to age-related neurodegeneration such as Alzheimer's disease (AD). Here, applying a state-of-the-art diffusion imaging processing pipeline and finite mixture modelling, we longitudinally examine the structural connectome of Supernormals. We find a unique structural connectome, containing the connections between frontal, cingulate, parietal, temporal, and subcortical regions in the same hemisphere that remains stable over time in Supernormals, relatively to typical agers. The connectome significantly classifies positive vs. negative AD pathology at 72% accuracy in a new sample mixing Supernormals, typical agers, and AD risk [amnestic mild cognitive impairment (aMCI)] subjects. Among this connectome, the mean diffusivity of the connection between right isthmus cingulate cortex and right precuneus most robustly contributes to predicting AD pathology across samples. The mean diffusivity of this connection links negatively to global cognition in those Supernormals with positive AD pathology. But this relationship does not exist in typical agers or aMCI. Our data suggest the presence of a structural connectome supporting cognitive success. Cingulate to precuneus white matter integrity may be useful as a structural marker for monitoring neurodegeneration and may provide critical information for understanding how some older adults maintain or excel cognitively in light of significant AD pathology.

Evaluating the Effect of Interleukin-4 in the 3xTg Mouse Model of Alzheimer's Disease.

Chronic neuroinflammation has long been hypothesized to be involved in Alzheimer's Disease (AD) progression. Previous research suggests that both anti-inflammatory and inflammatory microglia ameliorate amyloid pathology, but the latter worsen tau pathology. In this study, we sought to determine whether induction of arginase-1 positive microglia with the anti-inflammatory cytokine IL-4 modulates pathology in the 3xTg mouse model of AD. Our findings indicate that a single intracranial IL-4 injection positively modulated performance of 3xTg AD mice in a Novel Object Recognition task, and locally increased the levels of arginase-1 positive myeloid cells when assessed one-week post injection. Furthermore, immunohistochemical analysis revealed decreased tau phosphorylation in IL-4 injected animals; however, we were not able to detect significant changes in tau phosphorylation utilizing Western blot. Lastly, IL-4 injection did not appear to cause significant changes in amyloid ß load. In conclusion, acute intracranial IL-4 led to some positive benefits in the 3xTg mouse model of AD. Although more work remains, these results support therapeutic strategies aimed at modifying microglial activation states in neurodegenerative diseases.

Altered dorsal CA1 neuronal population coding in the APP/PS1 mouse model of Alzheimer's disease.

While the link between amyloid ß (Aß) accumulation and synaptic degradation in Alzheimer's disease (AD) is known, the consequences of this pathology on population coding remain unknown. We found that the entropy, a measure of the diversity of network firing patterns, was lower in the dorsal CA1 region in the APP/PS1 mouse model of Aß pathology, relative to controls, thereby reducing the population's coding capacity. Our results reveal a network level signature of the deficits Aß accumulation causes to the computations performed by neural circuits.