Showing papers by "Jacob Raber published in 2017"
TL;DR: A susceptibility of E4 carriers to metabolic impairments brought on by IR is suggested, and may guide development of novel therapies for cognitive decline and dementia.
Abstract: Apolipoprotein E4 (E4) and type 2 diabetes are major risk factors for cognitive decline and late onset Alzheimer’s disease (AD). E4-associated phenotypes and insulin resistance (IR) share several features and appear to interact in driving cognitive dysfunction. However, shared mechanisms that could explain their overlapping pathophysiology have yet to be found. We hypothesized that, compared to E3 mice, E4 mice would be more susceptible to the harmful cognitive effects of high fat diet (HFD)-induced IR due to apoE isoform-specific differences in brain metabolism. While both E3 and E4 mice fed HFD displayed impairments in peripheral metabolism and cognition, deficits in hippocampal-dependent spatial learning and memory were exaggerated in E4 mice. Combining genome-wide measures of DNA hydroxymethylation with comprehensive untargeted metabolomics, we identified novel alterations in purine metabolism, glutamate metabolism, and the pentose phosphate pathway. Finally, in E4 mice, the metabolic and cognitive deficiencies caused by HFD were rescued by switching to a low fat diet for one month, suggesting a functional role was associated with reversal of the same metabolic pathways described above. These results suggest a susceptibility of E4 carriers to metabolic impairments brought on by IR, and may guide development of novel therapies for cognitive decline and dementia.
67 citations
TL;DR: It is found that HA and CD44 play important roles in regulating adult neurogenesis, and evidence that HA contributes to age-related reductions in neural stem cell (NSC) expansion and differentiation in the hippocampus is provided.
54 citations
TL;DR: Although combined treatment with precision RT and checkpoint inhibitor IT achieved tumor growth control, it affected the brain and induced changes in measures of anxiety, cognitive impairments, and neuroinflammation.
Abstract: // Gwendolyn J. McGinnis 1, 2, 3 , David Friedman 4 , Kristina H. Young 4 , Eileen Ruth S. Torres 2 , Charles R. Thomas Jr 3 , Michael J. Gough 3, 4 , Jacob Raber 2, 3, 5, 6 1 Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR 2 Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 3 Department of Radiation Medicine, Oregon Health and Science University, Portland, OR 4 Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR 5 Department of Neurology, Oregon Health and Science University, Portland, OR 6 Division of Neuroscience, Oregon National Primate Research Center, Portland, OR Correspondence to: Jacob Raber, email: raberj@ohsu.edu Keywords: neuroinflammation, cancer-related neurological dysfunction, microglia, immunotherapy, radiotherapy Received: June 21, 2016 Accepted: November 14, 2016 Published: November 24, 2016 ABSTRACT Background: Cancer patients often report behavioral and cognitive changes following cancer treatment. These effects can be seen in patients who have not yet received treatment or have received only peripheral (non-brain) irradiation. Novel treatments combining radiotherapy (RT) and immunotherapy (IT) demonstrate remarkable efficacy with respect to tumor outcomes by enhancing the proinflammatory environment in the tumor. However, a proinflammatory environment in the brain mediates cognitive impairments in other neurological disorders and may affect brain function in cancer patients receiving these novel treatments. Currently, gaps exist as to whether these treatments impact the brain in individuals with or without tumors and with regard to the underlying mechanisms. Results: Combined treatment with precision RT and checkpoint inhibitor IT achieved control of tumor growth. However, BALB/c mice receiving combined treatment demonstrated changes in measures of anxiety levels, regardless of tumor status. C57BL/6J mice with tumors demonstrated increased anxiety, except following combined treatment. Object recognition memory was impaired in C57BL/6J mice without tumors following combined treatment. All mice with tumors showed impaired object recognition, except those treated with RT alone. Mice with tumors demonstrated impaired amygdala-dependent cued fear memory, while maintaining hippocampus-dependent context fear memory. These behavioral alterations and cognitive impairments were accompanied by increased microglial activation in mice receiving immunotherapy alone or combined with RT. Finally, based on tumor status, there were significant changes in proinflammatory cytokines (IFN-γ, IL-6, IL-5, IL-2, IL-10) and a growth factor (FGF-basic). Materials and Methods: Here we test the hypothesis that IT combined with peripheral RT have detrimental behavioral and cognitive effects as a result of an enhanced proinflammatory environment in the brain. BALB/c mice with or without injected hind flank CT26 colorectal carcinoma or C57BL/6J mice with or without Lewis Lung carcinoma were used for all experiments. Checkpoint inhibitor IT, using an anti-CTLA-4 antibody, and precision CT-guided peripheral RT alone and combined were used to closely model clinical treatment. We assessed behavioral and cognitive performance and investigated the immune environment using immunohistochemistry and multiplex assays to analyze proinflammatory mediators. Conclusions: Although combined treatment achieved tumor growth control, it affected the brain and induced changes in measures of anxiety, cognitive impairments, and neuroinflammation.
52 citations
TL;DR: The cognitive, metabolic and cerebrovascular responses to an exogenous glucose load showed an apoE isoform-dependent response, with E4, but not E3 mice, acutely benefiting from a spike in blood glucose.
Abstract: Metabolic dysfunction, commonly a result of diets high in saturated fats and sugar, is associated with impaired cognitive function and an increased risk of age-related cognitive decline (ACD) and Alzheimer's disease (AD). Compared to the E3 isoform of apolipoprotein (apoE), the E4 isoform is a major genetic risk factor for ACD, AD, and for developing cognitive impairments following various environmental challenges, including dietary challenges such as a high-fat diet (HFD). Both insulin resistance (IR) and E4 are associated with metabolic and vascular impairments. Deficits in cerebral metabolism and cerebrovascular function have been proposed as initiating events leading to these impairments. In the current study, we employed a model of human apoE targeted replacement mice and HFD-induced obesity to study the potential link between E4 and IR, at rest and following a postprandial challenge. HFD-induced IR was associated with impaired cognition, reduced cerebral blood volume and decreased glucose uptake. These effects were more profound in E4 than E3 mice. Furthermore, the cognitive, metabolic and cerebrovascular responses to an exogenous glucose load showed an apoE isoform-dependent response, with E4, but not E3 mice, acutely benefiting from a spike in blood glucose.
38 citations
TL;DR: This review considers the use of preclinical tumor-models to study the role of tumor status in CNS effects of immune checkpoint inhibitors and multimodality therapy, and discusses ongoing studies regarding the ability of immune checkpoints to reach the brain.
Abstract: Following cancer treatment, patients often report behavioral and cognitive changes. Novel cancer immunotherapeutics have the potential to produce sustained cancer survivorship, meaning patients will live longer with the side effects of treatment. Given the role of inflammatory pathways in mediating behavioral and cognitive impairments seen in cancer, we aim in this review to discuss emerging evidence for the contribution of immune checkpoint blockade to exacerbate these CNS effects. We discuss ongoing studies regarding the ability of immune checkpoint inhibitors to reach the brain and how treatment responses to checkpoint inhibitors may be modulated by genetic factors. We further consider the use of preclinical tumor-models to study the role of tumor status in CNS effects of immune checkpoint inhibitors and multimodality therapy.
34 citations
TL;DR: The brain’s response to proton irradiation is both specific and prolonged and involves novel remodeling of non-random regions of the epigenome.
Abstract: The brain's response to radiation exposure is an important concern for patients undergoing cancer therapy and astronauts on long missions in deep space. We assessed whether this response is specific and prolonged and is linked to epigenetic mechanisms. We focused on the response of the hippocampus at early (2-weeks) and late (20-week) time points following whole body proton irradiation. We examined two forms of DNA methylation, cytosine methylation (5mC) and hydroxymethylation (5hmC). Impairments in object recognition, spatial memory retention, and network stability following proton irradiation were observed at the two-week time point and correlated with altered gene expression and 5hmC profiles that mapped to specific gene ontology pathways. Significant overlap was observed between DNA methylation changes at the 2 and 20-week time points demonstrating specificity and retention of changes in response to radiation. Moreover, a novel class of DNA methylation change was observed following an environmental challenge (i.e. space irradiation), characterized by both increased and decreased 5hmC levels along the entire gene body. These changes were mapped to genes encoding neuronal functions including postsynaptic gene ontology categories. Thus, the brain's response to proton irradiation is both specific and prolonged and involves novel remodeling of non-random regions of the epigenome.
27 citations
TL;DR: The results are consistent with the hypothesis that NF1 functions in mice biochemically to inhibit signaling from Alk through Ras, and indicate that inhibition of Alk activity may cognitively benefit patients with Neurofibromatosis 1.
17 citations
TL;DR: Cognitive impairment of spatial memory retention observed in heterozygous NF1 mutant mice was rescued by the Alk inhibitor, supporting the hypothesis that inhibition of Alk may cognitively benefit patients with Neurofibromatosis 1.
15 citations
TL;DR: EUK‐207 has attractive properties and should be considered an ideal candidate to mitigate radiation‐induced cognitive injury.
8 citations
TL;DR: Results showed that exposure to 28Si TBI dramatically reduced the frequencies and numbers of HSCs in irradiated mice, compared to non-irradiated controls, in a radiation dose-dependent manner, and indicated that exposure of low doses of 28Si irradiation leads to acute HSC damage.
Abstract: Long-term space mission exposes astronauts to a radiation environment with potential health hazards. High-energy charged particles (HZE), including 28Si nuclei in space, have deleterious effects on cells due to their characteristics with high linear energy transfer and dense ionization. The influence of 28Si ions contributes more than 10% to the radiation dose equivalent in the space environment. Understanding the biological effects of 28Si irradiation is important to assess the potential health hazards of long-term space missions. The hematopoietic system is highly sensitive to radiation injury and bone marrow (BM) suppression is the primary life-threatening injuries after exposure to a moderate dose of radiation. Therefore, in the present study we investigated the acute effects of low doses of 28Si irradiation on the hematopoietic system in a mouse model. Specifically, 6-month-old C57BL/6J mice were exposed to 0.3, 0.6 and 0.9Gy 28Si (600MeV) total body irradiation (TBI). The effects of 28Si TBI on BM hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) were examined four weeks after the exposure. The results showed that exposure to 28Si TBI dramatically reduced the frequencies and numbers of HSCs in irradiated mice, compared to non-irradiated controls, in a radiation dose-dependent manner. In contrast, no significant changes were observed in BM HPCs regardless of radiation doses. Furthermore, irradiated HSCs exhibited a significant impairment in clonogenic ability. These acute effects of 28Si irradiation on HSCs may be attributable to radiation-induced apoptosis of HSCs, because HSCs, but not HPCs, from irradiated mice exhibited a significant increase in apoptosis in a radiation dose-dependent manner. However, exposure to low doses of 28Si did not result in an increased production of reactive oxygen species and DNA damage in HSCs and HPCs. These findings indicate that exposure to 28Si irradiation leads to acute HSC damage.
8 citations
TL;DR: MA and NIC exposure during early adolescence separately decreased anxiety‐like behavior in the open field test, which was not seen following co‐administration of MA/NIC, and there was no significant effect of early adolescent MA and/or NIC exposure on the intensity of MAP‐2 immunoreactivity in the nucleus accumbens or on plasma corticosterone levels.
TL;DR: Exome sequencing from a patient with neurological and developmental symptoms revealed a homozygous transition mutation that results in an in-frame, premature translational stop codon in the ZNF135 gene predicted to encode a transcriptional repressor.
Abstract: Exome sequencing from a patient with neurological and developmental symptoms revealed two mutations in separate genes. One was a homozygous transition mutation that results in an in-frame, premature translational stop codon in the ZNF135 gene predicted to encode a transcriptional repressor. Another mutation was heterozygous, a single nucleotide duplication in the KCNN2 gene that encodes a Ca-activated K channel, SK2, and leads to a translational frame shift and a premature stop codon. Heterologous expression studies, brain slice recordings, and coordination tests from a transgenic mouse line carrying the SK2 mutation suggest that it does not contribute to the patient's symptoms. ZNF135 is expressed in human brain and it is likely that the homozygous mutation underlies the human phenotype.
TL;DR: In humans, apoE, which plays a role in repair, is expressed in three isoforms: E2, E3, and E4, and these isoforms modulate the radiation response, which is mediated by reactive oxygen species (ROS) in an-apoE isoform-dependent fashion.
Abstract: // Laura E. Villasana 1 , Tunde Akinyeke 1 , Sydney Weber 1 and Jacob Raber 1, 2 1 Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR 97239, USA 2 Departments of Neurology and Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR 97239, USA Correspondence to: Jacob Raber, email: raberj@ohsu.edu Keywords: cognition, superoxide, DHE, hippocampus, NADPH Received: March 01, 2017 Accepted: August 17, 2017 Published: September 01, 2017 ABSTRACT In humans, apoE, which plays a role in repair, is expressed in three isoforms: E2, E3, and E4. E4 is a risk factor for age-related cognitive decline (ACD) and Alzheimer’s disease (AD), particularly in women. In contrast, E2 is a protective factor for ACD and AD. E2 and E4 might also differ in their response to cranial 137 Cs irradiation, a form of radiation typically used in a clinical setting for the treatment of cancer. This might be mediated by reactive oxygen species (ROS) in an-apoE isoform-dependent fashion. E2 and E4 female mice received sham-irradiation or cranial irradiation at 8 weeks of age and a standard mouse chow or a diet supplemented with the antioxidant alpha-lipoic acid (ALA) starting at 6 weeks of age. Behavioral and cognitive performance of the mice were assessed 12 weeks later. Subsequently, the generation of ROS in hippocampal slices was analyzed. Compared to sham-irradiated E4 mice, irradiated E4 mice showed enhanced spatial memory in the water maze. This was associated with increased hippocampal PMA-induction of ROS. Similar effects were not seen in E2 mice. Irradiation increased endogenous hippocampal ROS levels in E2 mice while decreasing those in E4 mice. NADPH activity and MnSOD levels were higher in sham-irradiated E2 than E4 mice. Irradiation increased NADPH activity and MnSOD levels in hemi brains of E4 mice but not in those of E2 mice. ALA did not affect behavioral and cognitive performance or hippocampal formation of ROS in either genotype. Thus, apoE isoforms modulate the radiation response.
TL;DR: C‐Myc protein was increased following acute ethanol exposure in a mouse knockout model and following chronic ethanol consumption in vervet monkeys and increased in animals that were acutely exposed to methamphetamine when compared to control treated animals, suggesting that in substance abuse c‐MyC plays an important role in the brain’s response.
TL;DR: The data indicate that whole body X ray irradiation of mice at 3 months of age causes persistent alterations in the fear response and activity levels in a novel environment, while the effects on body weight seem more transient.