Targeting Macrophages to Reduce Colorectal Cancer Metastasis: Diminished Effect in the Alcohol-injured Liver

https://digitalcommons.unmc.edu/surp2022/1012/thumbnail.jp

ApoE isoform-dependent changes in hippocampal synaptic function

The lipoprotein receptor system in the hippocampus is intimately involved in the modulation of synaptic transmission and plasticity. The association of specific apoE isoform expression with human neurodegenerative disorders has focused attention on the role of these apoE isoforms in lipoprotein receptor-dependent synaptic modulation. In the present study, we used the apoE2, apoE3 and apoE4 targeted replacement (TR) mice along with recombinant human apoE isoforms to determine the role of apoE isoforms in hippocampus area CA1 synaptic function. While synaptic transmission is unaffected by apoE isoform, long-term potentiation (LTP) is significantly enhanced in apoE4 TR mice versus apoE2 TR mice. ApoE isoform-dependent differences in LTP induction require NMDA-receptor function, and apoE isoform expression alters activation of both ERK and JNK signal transduction. Acute application of specific apoE isoforms also alters LTP induction while decreasing NMDA-receptor mediated field potentials. Furthermore, acute apoE isoform application does not have the same effects on ERK and JNK activation. These findings demonstrate specific, isoform-dependent effects of human apoE isoforms on adult hippocampus synaptic plasticity and highlight mechanistic differences between chronic apoE isoform expression and acute apoE isoform exposure

Introducing Human APOE into Aβ Transgenic Mouse Models

Apolipoprotein E (apoE) and apoE/amyloid-β (Aβ) transgenic (Tg) mouse models are critical to understanding apoE-isoform effects on Alzheimer's disease risk. Compared to wild type, apoE−/− mice exhibit neuronal deficits, similar to apoE4-Tg compared to apoE3-Tg mice, providing a model for Aβ-independent apoE effects on neurodegeneration. To determine the effects of apoE on Aβ-induced neuropathology, apoE−/− mice were crossed with Aβ-Tg mice, resulting in a significant delay in plaque deposition. Surprisingly, crossing human-apoE-Tg mice with apoE−/−/Aβ-Tg mice further delayed plaque deposition, which eventually developed in apoE4/Aβ-Tg mice prior to apoE3/Aβ-Tg. One approach to address hAPOE-induced temporal delay in Aβ pathology is an additional insult, like head injury. Another is crossing human-apoE-Tg mice with Aβ-Tg mice that have rapid-onset Aβ pathology. For example, because 5xFAD mice develop plaques by 2 months, the prediction is that human-apoE/5xFAD-Tg mice develop plaques around 6 months and 12 months before other human-apoE/Aβ-Tg mice. Thus, tractable models for human-apoE/Aβ-Tg mice continue to evolve

Soluble apoE/Aβ complex: mechanism and therapeutic target for APOE4-induced AD risk

The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer\u27s disease (AD) compared to APOE2 and APOE3. Amyloid-β (Aβ), particularly in a soluble oligomeric form (oAβ), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of soluble oAβ are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oAβ levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with Aβ, namely apoE/Aβ complex, modulate Aβ levels. Specifically, we propose that compared to apoE3, apoE4-containing lipoproteins are less lipidated, leading to less stable apoE4/Aβ complexes, resulting in reduced apoE4/Aβ levels and increased accumulation, particularly of oAβ. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed

Soluble apoE/Aβ Complex: Mechanism and Therapeutic target for APOE4-induced AD Risk

The APOE4 allele of apolipoprotein E (apoE) is the greatest genetic risk factor for Alzheimer\u27s disease (AD) compared to APOE2 and APOE3. Amyloid-β (Aβ), particularly in a soluble oligomeric form (oAβ), is considered a proximal cause of neurodegeneration in AD. Emerging data indicate that levels of soluble oAβ are increased with APOE4, providing a potential mechanism of APOE4-induced AD risk. However, the pathway(s) by which apoE4 may increase oAβ levels are unclear and the subject of continued inquiry. In this editorial review, we present the hypothesis that apoE isoform-specific interactions with Aβ, namely apoE/Aβ complex, modulate Aβ levels. Specifically, we propose that compared to apoE3, apoE4-containing lipoproteins are less lipidated, leading to less stable apoE4/Aβ complexes, resulting in reduced apoE4/Aβ levels and increased accumulation, particularly of oAβ. Evidence that support or counter this argument, as well as the therapeutic significance of this pathway to neurodegeneration, are discussed

Sardinia Radio Telescope wide-band spectral-polarimetric observations of the galaxy cluster 3C 129

We present new observations of the galaxy cluster 3C 129 obtained with the Sardinia Radio Telescope in the frequency range 6000-7200 MHz, with the aim to image the large-angular-scale emission at high-frequency of the radio sources located in this cluster of galaxies. The data were acquired using the recently-commissioned ROACH2-based backend to produce full-Stokes image cubes of an area of 1 deg x 1 deg centered on the radio source 3C 129. We modeled and deconvolved the telescope beam pattern from the data. We also measured the instrumental polarization beam patterns to correct the polarization images for off-axis instrumental polarization. Total intensity images at an angular resolution of 2.9 arcmin were obtained for the tailed radio galaxy 3C 129 and for 13 more sources in the field, including 3C 129.1 at the galaxy cluster center. These data were used, in combination with literature data at lower frequencies, to derive the variation of the synchrotron spectrum of 3C 129 along the tail of the radio source. If the magnetic field is at the equipartition value, we showed that the lifetimes of radiating electrons result in a radiative age for 3C 129 of t_syn = 267 +/- 26 Myrs. Assuming a linear projected length of 488 kpc for the tail, we deduced that 3C 129 is moving supersonically with a Mach number of M=v_gal/c_s=1.47. Linearly polarized emission was clearly detected for both 3C 129 and 3C 129.1. The linear polarization measured for 3C 129 reaches levels as high as 70% in the faintest region of the source where the magnetic field is aligned with the direction of the tail.Comment: 19 pages, 17 figures, accepted for publication in MNRA

Imaging of SNR IC443 and W44 with the Sardinia Radio Telescope at 1.5 GHz and 7 GHz

Observations of supernova remnants (SNRs) are a powerful tool for investigating the later stages of stellar evolution, the properties of the ambient interstellar medium, and the physics of particle acceleration and shocks. For a fraction of SNRs, multi-wavelength coverage from radio to ultra high-energies has been provided, constraining their contributions to the production of Galactic cosmic rays. Although radio emission is the most common identifier of SNRs and a prime probe for refining models, high-resolution images at frequencies above 5 GHz are surprisingly lacking, even for bright and well-known SNRs such as IC443 and W44. In the frameworks of the Astronomical Validation and Early Science Program with the 64-m single-dish Sardinia Radio Telescope, we provided, for the first time, single-dish deep imaging at 7 GHz of the IC443 and W44 complexes coupled with spatially-resolved spectra in the 1.5-7 GHz frequency range. Our images were obtained through on-the-fly mapping techniques, providing antenna beam oversampling and resulting in accurate continuum flux density measurements. The integrated flux densities associated with IC443 are S_1.5GHz = 134 +/- 4 Jy and S_7GHz = 67 +/- 3 Jy. For W44, we measured total flux densities of S_1.5GHz = 214 +/- 6 Jy and S_7GHz = 94 +/- 4 Jy. Spectral index maps provide evidence of a wide physical parameter scatter among different SNR regions: a flat spectrum is observed from the brightest SNR regions at the shock, while steeper spectral indices (up to 0.7) are observed in fainter cooling regions, disentangling in this way different populations and spectra of radio/gamma-ray-emitting electrons in these SNRs.Comment: 13 pages, 9 figures, accepted for publication to MNRAS on 18 May 201

Similar promotion of Aβ(1-42 )fibrillogenesis by native apolipoprotein E ε3 and ε4 isoforms

The apolipoprotein E ε4 allele contributes to the genetic susceptibility underlying a large proportion (~40–60%) of typical, sporadic Alzheimer disease. Apolipoprotein E deficient mice made transgenic for human apolipoprotein E ε4 accumulate excess cerebral amyloid when compared to similarly prepared mice expressing human apolipoprotein E ε3. Therefore, it is important to search for relevant interactions(s) between apolipoprotein E ε4 and Aβ in order to clarify the biological role for apolipoprotein E ε4 in Alzheimer disease. Using a thioflavine T (ThT)-based assay, we have investigated the effects of native human apolipoprotein E isoforms on the kinetics of Aβ fibrillogenesis. No obvious profibrillogenic activity was detected in Aβ(1-40)-based assays of any native apolipoprotein E isoform. However, when ThT assays were repeated using Aβ(1-42), modest, but statistically significant, profibrillogenic activity was detected in both apolipoprotein E ε3- and apolipoprotein E ε4-containing media and was similar in magnitude for the two isoforms. These data demonstrate that native apolipoprotein E possesses "pathological chaperone"-type activity for Aβ: in other words, the data indicate that a chaperone-like misfolding reaction can occur between native apolipoprotein E and Aβ. However, the equipotent activities of the apolipoprotein E ε3 and ε4 isoforms suggests the possibility that either extended co-incubation of apolipoprotein E and Aβ, or, perhaps, the inclusion in the reaction of other fibrillogenesis-modulation co-factors (such as metal ions, or inflammatory mediators such as reactive oxygen species, α(2)-macroglobulin, apolipoprotein J, etc.) may be required for modeling in vitro the apolipoprotein E-isoform-specific-regulation of extracellular Aβ accumulation that occurs in vivo. Alternatively, other events, such as differential apolipoprotein E-isoform-mediated clearance of Aβ or of apolipoprotein E/Aβ complexes may underlie apolipoprotein E-isoform-dependent Aβ accumulation

Ultrasonographic assessment of spleen size and pattern of change among sickle cell disease patients and healthy controls in North-Eastern Nigeria

Background: Ultrasonography is an established and reliable method for assessing the spleen. Because of variation due to genetic and other environmental factors including malaria endemicity, interpretation of spleen sizes requires a knowledge of the normal reference range for a given population. This study aimed to identify spleen size reference ranges across age groups of healthy controls to serve as a baseline to assess changes in spleen size in patients with sickle cell disease. Methods: Using a cross-sectional study design, spleen size was measured in healthy people of different age groups and steady-state sickle cell disease patients (children and adults) using abdominal ultrasonography. Using the age-group-specific reference values obtained from the controls, spleens were classified into small, normal size or enlarged among the sickle cell disease patients. Results: The study consisted of 109 (34.8%) healthy controls and 204 (65.2%) steady-state sickle cell disease patients. The spleen was visualised in all the controls ( n = 109) and in 107 (52.4%) sickle cell disease patients. Using cut-off values for spleen length among the controls across age groups (< 5 years (5.0–7.0 cm); 5–9 years (5.5–8.5 cm); 10–14 years (6.0–11.0 cm) and ⩾ 15 years (7.0–12.5 cm)), spleen size was classified as small ( n = 18/204; 8.87%), normal ( n = 68/204; 33.3%) and enlarged ( n = 21/204; 10.3%) among the sickle cell disease patients. Conclusion: Model-based age-group reference ranges and percentile curves for splenic dimensions based on ultrasonography among normal controls in North-Eastern Nigeria were established and may be of value in assessing spleen sizes among sickle cell disease patients living in malaria-endemic regions of Africa

Intraneuronal Aβ detection in 5xFAD mice by a new Aβ-specific antibody

<p>Abstract</p> <p>Background</p> <p>The form(s) of amyloid-β peptide (Aβ) associated with the pathology characteristic of Alzheimer's disease (AD) remains unclear. In particular, the neurotoxicity of intraneuronal Aβ accumulation is an issue of considerable controversy; even the existence of Aβ deposits within neurons has recently been challenged by Winton and co-workers. These authors purport that it is actually intraneuronal APP that is being detected by antibodies thought to be specific for Aβ. To further address this issue, an anti-Aβ antibody was developed (MOAB-2) that specifically detects Aβ, but not APP. This antibody allows for the further evaluation of the early accumulation of intraneuronal Aβ in transgenic mice with increased levels of human Aβ in 5xFAD and 3xTg mice.</p> <p>Results</p> <p>MOAB-2 (mouse IgG_2b) is a pan-specific, high-titer antibody to Aβ residues 1-4 as demonstrated by biochemical and immunohistochemical analyses (IHC), particularly compared to 6E10 (a commonly used commercial antibody to Aβ residues 3-8). MOAB-2 did not detect APP or APP-CTFs in cell culture media/lysates (HEK-APP_Sweor HEK-APP_Swe/BACE1) or in brain homogenates from transgenic mice expressing 5 familial AD (FAD) mutation (5xFAD mice). Using IHC on 5xFAD brain tissue, MOAB-2 immunoreactivity co-localized with C-terminal antibodies specific for Aβ40 and Aβ42. MOAB-2 did not co-localize with either N- or C-terminal antibodies to APP. In addition, no MOAB-2-immunreactivity was observed in the brains of 5xFAD/BACE^-/-mice, although significant amounts of APP were detected by N- and C-terminal antibodies to APP, as well as by 6E10. In both 5xFAD and 3xTg mouse brain tissue, MOAB-2 co-localized with cathepsin-D, a marker for acidic organelles, further evidence for intraneuronal Aβ, distinct from Aβ associated with the cell membrane. MOAB-2 demonstrated strong intraneuronal and extra-cellular immunoreactivity in 5xFAD and 3xTg mouse brain tissues.</p> <p>Conclusions</p> <p>Both intraneuronal Aβ accumulation and extracellular Aβ deposition was demonstrated in 5xFAD mice and 3xTg mice with MOAB-2, an antibody that will help differentiate intracellular Aβ from APP. However, further investigation is required to determine whether a molecular mechanism links the presence of intraneuronal Aβ with neurotoxicity. As well, understanding the relevance of these observations to human AD patients is critical.</p