A Preliminary Report: The Hippocampus and Surrounding Temporal Cortex of Patients With Schizophrenia Have Impaired Blood-Brain Barrier

Schizophrenia (SZ) is one of the most severe forms of mental illness, yet mechanisms remain unclear. A widely established brain finding in SZ is hippocampal atrophy, and a coherent explanation similarly is lacking. Epidemiological evidence suggests increased cerebrovascular and cardiovascular complications in SZ independent of lifestyle and medication, pointing to disease-specific pathology. Endothelial cell contributions to blood-brain barrier (BBB) compromise may influence neurovascular unit and peripheral vascular function, and we hypothesize that downstream functional and structural abnormalities may be explained by impaired BBB

Evidence That Brain-Reactive Autoantibodies Contribute to Chronic Neuronal Internalization of Exogenous Amyloid-β1-42 and Key Cell Surface Proteins During Alzheimer\u27s Disease Pathogenesis

Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer\u27s disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro. Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid-β1-42 (Aβ42), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (α7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of Aβ42, IgG, GluR2/3, and α7nAChR as well as lysosomal compartment expansion in these cells in regions of AD pathology. To test possible mechanistic interrelationships of these phenomena, we exposed differentiated SH-SY5Y neuroblastoma cells to exogenous, soluble Aβ42 peptide and serum from AD and control subjects. The rate and extent of Aβ42 internalization in these cells was enhanced by serum containing neuron-binding IgG autoantibodies. This was confirmed by treating cells with individual antibodies specific for α7nAChR, purified IgG from AD or non-AD sera, and sera devoid of IgG, in the presence of 100 nM Aβ42. Initial co-localization of IgG, α7nAChR, and Aβ42 was temporally and spatially linked to early endosomes (Rab11) and later to lysosomes (LAMP-1). Aβ42 internalization was attenuated by treatment with monovalent F(ab) antibody fragments generated from purified IgG from AD serum and then rescued by coupling F(ab) fragments with divalent human anti-Fab. Overall, results suggest that cross-linking of neuron-binding autoantibodies targeting cell surface proteins can accelerate intraneuronal Aβ42 deposition in AD

TREASUREHUNT: Transients and Variability Discovered with HST in the JWST North Ecliptic Pole Time-domain Field

The James Webb Space Telescope (JWST) North Ecliptic Pole (NEP) Time-domain Field (TDF) is a >14′ diameter field optimized for multiwavelength time-domain science with JWST. It has been observed across the electromagnetic spectrum both from the ground and from space, including with the Hubble Space Telescope (HST). As part of HST observations over three cycles (the “TREASUREHUNT” program), deep images were obtained with the Wide Field Camera on the Advanced Camera for Surveys in F435W and F606W that cover almost the entire JWST NEP TDF. Many of the individual pointings of these programs partially overlap, allowing an initial assessment of the potential of this field for time-domain science with HST and JWST. The cumulative area of overlapping pointings is ∼88 arcmin2, with time intervals between individual epochs that range between 1 day and 4+ yr. To a depth of m AB ≃ 29.5 mag (F606W), we present the discovery of 12 transients and 190 variable candidates. For the variable candidates, we demonstrate that Gaussian statistics are applicable and estimate that ∼80 are false positives. The majority of the transients will be supernovae, although at least two are likely quasars. Most variable candidates are active galactic nuclei (AGNs), where we find 0.42% of the general z ≲ 6 field galaxy population to vary at the ∼3σ level. Based on a 5 yr time frame, this translates into a random supernova areal density of up to ∼0.07 transients arcmin−2 (∼245 deg−2) per epoch and a variable AGN areal density of ∼1.25 variables arcmin−2 (∼4500 deg−2) to these depths

Age-dependent increase of blood-brain barrier permeability and neuron-binding autoantibodies in S100B knockout mice

Abstract S100B is a calcium-sensor protein that impacts multiple signal transduction pathways. It is widely considered to be an important biomarker for several neuronal diseases as well as blood-brain barrier (BBB) breakdown. In this report, we demonstrate a BBB deficiency in mice that lack S100B through detection of leaked Immunoglobulin G (IgG) in the brain parenchyma. IgG leaks and IgG-binding to selected neurons were observed in S100B knockout (S100BKO) mice at 6 months of age but not at 3 months. By 9 months, IgG leaks persisted and the density of IgG-bound neurons increased significantly. These results reveal a chronic increase in BBB permeability upon aging in S100BKO mice for the first time. Moreover, coincident with the increase in IgG-bound neurons, autoantibodies targeting brain proteins were detected in the serum via western blots. These events were concurrent with compromise of neurons, increase of activated microglia and lack of astrocytic activation as evidenced by decreased expression of microtubule-associated protein type 2 (MAP2), elevated number of CD68 positive cells and unaltered expression of glial fibrillary acidic protein (GFAP) respectively. Results suggest a key role for S100B in maintaining BBB functional integrity and, further, propose the S100BKO mouse as a valuable model system to explore the link between chronic functional compromise of the BBB, generation of brain-reactive autoantibodies and neuronal dysfunctions

Natural IgG Autoantibodies Are Abundant and Ubiquitous in Human Sera, and Their Number Is Influenced By Age, Gender, and Disease

<div><p>The presence of self-reactive IgG autoantibodies in human sera is largely thought to represent a breakdown in central tolerance and is typically regarded as a harbinger of autoimmune pathology. In the present study, immune-response profiling of human serum from 166 individuals via human protein microarrays demonstrates that IgG autoantibodies are abundant in all human serum, usually numbering in the thousands. These IgG autoantibodies bind to human antigens from organs and tissues all over the body and their serum diversity is strongly influenced by age, gender, and the presence of specific diseases. We also found that serum IgG autoantibody profiles are unique to an individual and remarkably stable over time. Similar profiles exist in rat and swine, suggesting conservation of this immunological feature among mammals. The number, diversity, and apparent evolutionary conservation of autoantibody profiles suggest that IgG autoantibodies have some important, as yet unrecognized, physiological function. We propose that IgG autoantibodies have evolved as an adaptive mechanism for debris-clearance, a function consistent with their apparent utility as diagnostic indicators of disease as already established for Alzheimer’s and Parkinson’s diseases.</p> </div

Serum IgG autoantibodies consistently bind to diverse antigens in many human organs. A.

<p>Human liver, kidney, lung, and brain tissue lysates were separated by SDS-PAGE and then probed with human serum. As indicated by the many immunoreactive protein bands of differing molecular weights, serum IgG autoantibodies bind to a variety of common and organ-specific SDS-denatured antigens. <b>B</b>. In western blots, proteins from human brain extract were probed with human serum (HS-I and HS-II) as primary antibodies. Serum samples at three timepoints, T1, T2 and T3, were collected from the same individual (HS-I) over a period of four years. Serum samples T1’ and T2’ were collected from a different individual (HS-II) over a period of two years. Consistent patterns of serum IgG immunoreactivity were specific to individuals and appeared to remain stable over time.</p

Dot blot confirmation of serum IgG auto-reactivity.

<p>Two identified antigens of serum autoantibodies, PTCD2 and ICAM4, were spotted onto nitrocellulose and probed with serum identical to that used on the protein microarrays. Serial dilution with diminishing immunoreactivity confirmed the presence and activity of IgG autoantibodies in human sera.</p

Serum IgG autoantibodies are detected in all mammals tested.

<p><b>A</b>. Pig, human, and rat brain lysates were separated by SDS-PAGE and then probed with their respective species-specific serum as a primary antibody. Each species possessed IgG autoantibodies that bound to a variety of SDS-denatured brain self-antigens. <b>B</b>. Proteins from pig brain extract were probed with serum collected from a single pig at two timepoints, TP1 and TP2, spanning three months. The majority of the pig auto-reactive IgG antibodies remain the same.</p

Representative autoantibody data showing their relative abundance in healthy individuals.

<p>An example of the reactions of four highly prevalent autoantibodies in a population of healthy subjects is presented. The X axis indicates individual samples arranged in order of increasing age from left to right. Relative fluorescence units (RFUs) (Y axis) reflect the resulting antigen-antibody reaction detected on the protein microarrays. Four specific autoantigens [tripartite motif-containing 21 (TRIM21), APEX nuclease (apurinic/apyrimidinic endonuclease) 2 (APEX2), General transcription factor II-I and SERPINE1 mRNA binding protein 1 (SERBP1)] were chosen due to their high prevalence in > 60% of the healthy population. The clear lamination of signal intensities shown by each autoantibody-antigen reaction suggests comparable levels of these autoantibodies in the blood across the population</p

Effects of Age and Gender on Autoantibody Count.

<p>A total of 57 normal healthy controls were split into three age groups and two gender groups. The percentage of female subjects in each group is indicated. A Z-factor of greater than 0.4 was used to define a positive antibody response. The mean and standard deviation of antibody counts are shown. The difference of the antibody counts between indicated groups were tested by student t test and p value as shown.</p