Showing papers by "Jacob Raber published in 2020"

Effects of Six Sequential Charged Particle Beams on Behavioral and Cognitive Performance in B6D2F1 Female and Male Mice.

Abstract: The radiation environment astronauts are exposed to in deep space includes galactic cosmic radiation (GCR) with different proportions of all naturally occurring ions. To assist NASA with assessment of risk to the brain following exposure to a mixture of ions broadly representative of the GCR, we assessed the behavioral and cognitive performance of female and male C57BL/6J × DBA2/J F1 (B6D2F1) mice two months following rapidly delivered, sequential 6 beam irradiation with protons (1 GeV, LET = 0.24 keV, 50%), 4He ions (250 MeV/n, LET = 1.6 keV/μm, 20%), 16O ions (250 MeV/n, LET = 25 keV/μm 7.5%), 28Si ions (263 MeV/n, LET = 78 keV/μm, 7.5%), 48Ti ions (1 GeV/n, LET = 107 keV/μm, 7.5%), and 56Fe ions (1 GeV/n, LET = 151 keV/μm, 7.5%) at 0, 25, 50, or 200 cGy) at 4-6 months of age. When the activity over 3 days of open field habituation was analyzed in female mice, those irradiated with 50 cGy moved less and spent less time in the center than sham-irradiated mice. Sham-irradiated female mice and those irradiated with 25 cGy showed object recognition. However, female mice exposed to 50 or 200 cGy did not show object recognition. When fear memory was assessed in passive avoidance tests, sham-irradiated mice and mice irradiated with 25 cGy showed memory retention while mice exposed to 50 or 200 cGy did not. The effects of radiation passive avoidance memory retention were not sex-dependent. There was no effect of radiation on depressive-like behavior in the forced swim test. There was a trend toward an effect of radiation on BDNF levels in the cortex of males, but not for females, with higher levels in male mice irradiated with 50 cGy than sham-irradiated. Finally, sequential 6-ion irradiation impacted the composition of the gut microbiome in a sex-dependent fashion. Taxa were uncovered whose relative abundance in the gut was associated with the radiation dose received. Thus, exposure to sequential six-beam irradiation significantly affects behavioral and cognitive performance and the gut microbiome.

Insulin BBB pharmacokinetics in young apoE male and female transgenic mice

Abstract: In addition to age, apolipoprotein E4 (E4), female sex, or a combination of both synergistically increase the risk for the development of Alzheimer's disease (AD). Why these risk factors predispose an individual to developing AD later in life is the target of the current investigation. Central nervous system (CNS) insulin resistance is associated with cognitive impairment and AD. CNS insulin is acquired primarily from the circulation and therefore must negotiate the blood-brain barrier (BBB). Thus, changes in BBB transport of insulin could lead to alterations in CNS insulin signaling and resistance, which would then lead to changes in cognition. There has been recent evidence suggesting the relationship between CNS insulin; E4, a risk factor to develop AD as compared to E3; and the female sex in aged individuals and in pre-clinical models. However, this relationship has been largely unexplored at a younger age, in which some of these risk factors could predispose an individual to dysregulation of CNS insulin later in life. Here, we present the first findings of BBB insulin pharmacokinetics in young E3 and E4 male and female targeted replacement (TR) mice. We found that levels of insulin binding the vasculature at the BBB are different due to genotype and sex which could impact the function of the brain endothelial cell. These early alterations could contribute to or fully explain the age-related cognitive changes observed due to CNS insulin signaling in E4 and/or female individuals.

Longitudinal Effects of Immediate and Delayed Estradiol on Cognitive Performance in a Spatial Maze and Hippocampal Volume in Menopausal Macaques Under an Obesogenic Diet.

Abstract: The consumption of a diet high in fat and refined sugars has several health risks, including the development of cognitive decline and neurodegeneration For women, menopause carries additional health risks that may interact with a high-fat diet in negative ways Some symptoms of menopause, including cognitive impairments, can be modulated by hormone replacement therapy (HRT), but the hormonal formulation and the timing of the treatment relative to the onset of menopause are critical factors determining its efficacy Little is known about how obesogenic, high-fat, high-sugar diets interact with HRT in menopause to affect cognition and neurodegeneration Given the high prevalence of the consumption of an obesogenic Western-style diet, understanding how the effects of HRT are modulated by an obesogenic diet is critical for developing optimized therapeutic strategies for peri- and post-menopausal women In this study, we investigated by magnetic resonance imaging (MRI) the effects of either immediate or delayed estradiol hormone therapy on cognition and neuroanatomy following ovo-hysterectomy (OvH) of aged, female rhesus macaques on an obesogenic diet The macaques were followed for 25 years after ovo-hysterectomy, with four time points at which anatomical MRIs were acquired Analysis of hippocampal volumes revealed an interaction between time point and treatment; hippocampal volumes in the delayed estrogen group, but not the immediate estrogen group, increased over time compared to those in untreated controls Performance on a hippocampal-dependent spatial maze task showed improved performance in estrogen treated animals compared to OvH macaques given placebo These results indicate that HRT may contribute to beneficial cognitive outcomes after menopause under an obesogenic diet

The S1 protein of SARS-CoV-2 crosses the blood-brain barrier: Kinetics, distribution, mechanisms, and influence of ApoE genotype, sex, and inflammation

Abstract: Evidence strongly suggests that SARS-CoV-2, the cause of COVID-19, can enter the brain. SARS-CoV-2 enters cells via the S1 subunit of its spike protein, and S1 can be used as a proxy for the uptake patterns and mechanisms used by the whole virus; unlike studies based on productive infection, viral proteins can be used to precisely determine pharmacokinetics and biodistribution. Here, we found that radioiodinated S1 (I-S1) readily crossed the murine blood-brain barrier (BBB). I-S1 from two commercial sources crossed the BBB with unidirectional influx constants of 0.287 ± 0.024 μL/g-min and 0.294 ± 0.032 μL/g-min and was also taken up by lung, spleen, kidney, and liver. I-S1 was uniformly taken up by all regions of the brain and inflammation induced by lipopolysaccharide reduced uptake in the hippocampus and olfactory bulb. I-S1 crossed the BBB completely to enter the parenchymal brain space, with smaller amounts retained by brain endothelial cells and the luminal surface. Studies on the mechanisms of transport indicated that I-S1 crosses the BBB by the mechanism of adsorptive transcytosis and that the murine ACE2 receptor is involved in brain and lung uptake, but not that by kidney, liver, or spleen. I-S1 entered brain after intranasal administration at about 1/10th the amount found after intravenous administration and about 0.66% of the intranasal dose entered blood. ApoE isoform or sex did not affect whole brain uptake, but had variable effects on olfactory bulb, liver, spleen, and kidney uptakes. In summary, I-S1 readily crosses the murine BBB, entering all brain regions and the peripheral tissues studied, likely by the mechanism of adsorptive transcytosis. Graphical

ApoE isoform-specific differences in behavior and cognition associated with subchronic MPTP exposure

Abstract: Parkinson's disease (PD) is characterized clinically by progressive motor dysfunction; overt parkinsonism is often preceded by prodromal symptoms including disturbances in the sleep-wake cycle. Up to 80% of patients with PD also develop dementia. In humans, there are three major apolipoprotein E isoforms: E2, E3, and E4. Increased rate of dementia in PD may be associated with E4 isoform. To better understand prodromal changes associated with E4, we exposed young (3-5 mo) male and female mice expressing E3 or E4 via targeted replacement to a subchronic dosage of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We hypothesized that E4 mice would be more susceptible to MPTP-related behavioral and cognitive changes. MPTP-treated E4 mice explored novel objects longer than genotype-matched saline-treated mice. In contrast, saline-treated E3 mice preferentially explored the novel object whereas MPTP-treated E3 mice did not and showed impaired object recognition. MPTP treatment altered swim speed of E4, but not E3, mice in the water maze compared to controls. Thus, E4 carriage may influence the preclinical symptoms associated with PD. Increased efforts are warranted to study early time points in this disease model.

Antisense oligonucleotides targeting alpha-synuclein reduce pre-formed fibril-induced Lewy pathology and improve some domains of cognitive and motor performance

Abstract: Alpha-synuclein (αsyn) is a small protein involved in neurodegenerative diseases known as synucleinopathies. The phosphorylated form (psyn) is the primary component of protein aggregates known as Lewy bodies (LBs), which are the hallmark of diseases such as Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Synucleinopathies might spread in a prion-like fashion, leading to a progressive emergence of symptoms over time. αsyn pre-formed fibrils (PFFs) induce LB-like pathology in wild-type (WT) mice, but there are remaining questions about the progressive “spreading” of pathology and the cognitive and behavioral effects. Here, we induced LB-like pathology in the bilateral motor cortex of WT mice and assessed behavioral and cognitive performance. As there are no long-term effective treatments for synucleinopathies, and no therapies slow or reduce the spreading of LBs, we also assessed the effects of a mouse αsyn-targeted antisense oligonucleotides (ASOs) on pathology and behavioral and cognitive performance starting 5 weeks after ASO treatment. At 3 months post-PFF injection (mpi), mice injected with PFFs showed cognitive impairments and mild motor impairments. At 6 mpi, PFF-injected mice showed further cognitive and motor impairments that were partially ameliorated by the ASO. ASO treatment also reduced LB-like pathology, and pathology was significantly correlated with cognitive measures. However, the particular mouse ASO used in these assays was also associated with some possible off-target effects, defined as effects not involving lowering of αsyn, such as a decline in body weight. These results add to what is known about the progressive nature of the PFF model of synucleinopathies. These data also support the therapeutic potential of ASOs to improve Lewy pathology and associated behavioral and cognitive phenotypes.