BACKGROUND: Cerebral amyloid angiopathy (CAA) is characterized by amyloid-β (Aβ) deposition in cerebral vessels, leading to lobar cerebral microbleeds (CMB) and intracerebral hemorrhages (ICH). Apolipoprotein J (ApoJ) is a multifunctional chaperone related to Aβ aggregation and clearance. Our study investigated the vascular impact of chronic recombinant human Apolipoprotein J (rhApoJ) treatment in a transgenic mouse model of β-amyloidosis with prominent CAA.
METHODS: Twenty-month-old APP23 C57BL/6 mice received 25 doses of rhApoJ (1 mg/kg) (n = 9) or saline (n = 8) intraperitoneally for 13 weeks, while Wild-type (WT) mice received saline (n = 13). Postmortem brains underwent T2*-weighted magnetic resonance imaging (MRI) to detect hemorrhagic lesions. Aβ levels and distribution, cerebral fibrinogen leakage, brain smooth muscle actin (sma), and plasma matrix metalloproteinases and inflammatory markers were analyzed after treatments. Additionally, plasma samples from 22 patients with lobar ICH were examined to determine the clinical relevance of the preclinical findings.
RESULTS: rhApoJ-treated APP23 presented fewer cortical CMBs (50-300 μm diameter) (p = 0.012) and cortical larger hemorrhages (> 300 μm) (p = 0.002) than saline-treated mice, independently of Aβ brain levels. MRI-detected hemorrhagic lesions correlated with fibrinogen cerebral extravasation (p = 0.011). Additionally, rhApoJ-treated mice presented higher number of sma-positive vessels than saline-treated mice (p = 0.038). In rhApoJ-treated mice, human ApoJ was detected in plasma and in occasional leptomeningeal vessels, but not in the parenchyma, suggesting that its mechanism of action operates through the periphery. The administration of rhApoJ induced an increase in plasma Groα (p = 0.035) and MIP-1α (p = 0.035) levels, while lower MMP-12 (p = 0.046) levels, compared to the saline-treated group. In acute lobar ICH patients, MMP-12 plasma levels correlated with larger hemorrhage volume (p = 0.040) and irregular ICH shape (p = 0.036).
CONCLUSIONS: Chronic rhApoJ treatment in aged APP23 mice ameliorated CAA-related neurovascular damage by reducing the occurrence of CMB. We propose that rhApoJ may prevent blood-brain barrier (BBB) leakage and CMB appearance partly through circulating MMP-12 modulation.

Diabetic patients present increased volume and functional alterations in epicardial adipose tissue (EAT). We aimed to analyze EAT from type 2 diabetic patients and the inflammatory and cytotoxic effects induced on cardiomyocytes. Furthermore, we analyzed the cardioprotective role of apolipoprotein J (apoJ). EAT explants were obtained from nondiabetic patients (ND), diabetic patients without coronary disease (DM), and DM patients with coronary disease (DM-C) after heart surgery. Morphological characteristics and gene expression were evaluated. Explants were cultured for 24 h and the content of nonesterified fatty acids (NEFA) and sphingolipid species in secretomes was evaluated by lipidomic analysis. Afterwards, secretomes were added to AC16 human cardiomyocytes for 24 h in the presence or absence of cardioprotective molecules (apoJ and HDL). Cytokine release and apoptosis/necrosis were assessed by ELISA and flow cytometry. The EAT from the diabetic samples showed altered expression of genes related to lipid accumulation, insulin resistance, and inflammation. The secretomes from the DM samples presented an increased ratio of pro/antiatherogenic ceramide (Cer) species, while those from DM-C contained the highest concentration of saturated NEFA. DM and DM-C secretomes promoted inflammation and cytotoxicity on AC16 cardiomyocytes. Exogenous Cer16:0, Cer24:1, and palmitic acid reproduced deleterious effects in AC16 cells. These effects were attenuated by exogenous apoJ. Diabetic secretomes promoted inflammation and cytotoxicity in cardiomyocytes. This effect was exacerbated in the secretomes of the DM-C samples. The increased content of specific NEFA and ceramide species seems to play a key role in inducing such deleterious effects, which are attenuated by apoJ.

UNASSIGNED: Apolipoproteins and contactin 5 are proteins associated with Alzheimer\'s disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment.
UNASSIGNED: To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage.
UNASSIGNED: Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink\'s proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of cognitively unimpaired participants (n = 93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (n = 57) and control subjects (n = 31) and in the hippocampi of mice following entorhinal cortex lesions.
UNASSIGNED: Contactin 5 positively correlated with apolipoproteins B (p = 5.4×10-8), D (p = 1.86×10-4), E (p = 2.92×10-9), J (p = 2.65×10-9), and with cholesterol (p = 0.0096) in the CSF, and with cholesterol (p = 0.02), HDL (p = 0.0143), and LDL (p = 0.0121) in the plasma. Negative correlations were seen between CNTN5, APOB (p = 0.034) and APOE (p = 0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (p <  0.05), while apob (p = 0.023) and apod (p = 0.006) increased in the deafferentation stage.
UNASSIGNED: Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage.

The perplex interrelation between circulating extracellular vesicles (cEVs) and amyloid-β (Aβ) deposits in the context of Alzheimer\'s disease (AD) is poorly understood.
This study aims to 1) analyze the possible cross-linkage of the neurotoxic amyloid-β oligomers (oAβ) to the human cEVs, 2) identify cEVs corona proteins associated with oAβ binding, and 3) analyze the distribution and expression of targeted cEVs proteins in preclinical participants converted to AD 5 years later (Pre-AD).
cEVs were isolated from 15 Pre-AD participants and 15 healthy controls selected from the Canadian Study of Health and Aging. Biochemical, clinical, lipid, and inflammatory profiles were measured. oAβ and cEVs interaction was determined by nanoparticle tracking analysis and proteinase K digestion. cEVs bound proteins were determined by ELISA.
oAβ were trapped by cEVs and were topologically bound to their external surface. We identified surface-exposed proteins functionally able to conjugate oAβ including apolipoprotein J (apoJ), apoE and RAGE, with apoJ being 30- to 130-fold higher than RAGE and apoE, respectively. The expression of cEVs apoJ was significantly lower in Pre-AD up to 5 years before AD onset.
Our findings suggest that cEVs might participate in oAβ clearance and that early dysregulation of cEVs could increase the risk of conversion to AD.

暂无摘要。

UNASSIGNED: Heart surgery results in complement activation with the potential for collateral end-organ damage, especially if the protective elements (complement factor H, Apolipoprotein J) are inadequate. Here, we have investigated if peri-operative stress results in an imbalance between complement activation and its protective mechanisms up to 3 months after heart surgery.
UNASSIGNED: 101 patients scheduled for non-emergent cardiac surgery donated blood before the procedure (tbaseline), and 24 h (t24h ), 7 days (t7d ) and 3 months (t3m ) after. Complement activation was measured as a serum level of soluble activated component 5 (sC5a) and soluble terminal complement complex (sTCC). Simultaneously, protective complement factor H (CfH), and apolipoprotein J (ApoJ) were measured. Inflammatory responses were quantified using C-reactive protein (CRP) and interleukin-6 (IL-6). Details regarding anesthesia, intensive care unit (ICU) stay, pre-existing conditions, the incidence of postoperative complications, and mortality were collected from medical records.
UNASSIGNED: C5a declined at t24h to rebound at t7d and t3m . sTCC was significantly depressed at t24h and returned to baseline at later time points. In contrast, CfH and ApoJ were depressed at t3m . Milieu of complement factors aligned along two longitudinal patterns:cluster#1 (C5a/sTTC continuously increasing and CfH/ApoJ preserved at tbaseline) and cluster#2 (transient sC5a/sTTC increase and progressive decline of CfH). Most patients belonged to cluster #1 at t24h (68%), t7d (74%) and t3m (72%). sTCC correlated with APACHE1h (r 2 =-0.25; p < 0.031) and APACHE24h (r 2 = 0.27; p < 0.049). IL-6 correlated with C5a (r 2 =-0.28; p < 0.042) and sTTC (r 2 =-0.28; p < 0.015). Peri-operative administration of acetaminophen and aspirin altered the complement elements. Prolonged hospital stay correlated with elevated C5a [t (78) = 2.03; p = 0.048] and sTTC serum levels [U (73) = 2.07; p = 0.037]. Patients with stroke had a decreased serum level of C5a at t7d and t3m.
UNASSIGNED: There is a significant decrease in complement protective factors 3 months after cardiac surgery, while C5a seems to be slightly elevated, suggesting that cardiac surgery affects complement milieu long into recovery.

Alzheimer\'s disease (AD) is the most common neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) aggregates in the brain. Clusterin (CLU), also known as apolipoprotein J, is a potent risk factor associated with AD pathogenesis, in which Aβ aggregation is essentially involved. We observed close colocalization of CLU and Aβ(1-42) (Aβ42) in parenchymal amyloid plaques or vascular amyloid deposits in the brains of human amyloid precursor protein (hAPP)-transgenic Tg2576 mice. Therefore, to elucidate the binding interaction between CLU and Aβ42 and its impact on amyloid aggregation and toxicity, the two synthetic proteins were incubated together under physiological conditions, and their structural and morphological variations were investigated using biochemical, biophysical, and microscopic analyses. Synthetic CLU spontaneously bound to different possible variants of Aβ42 aggregates with very high affinity (Kd = 2.647 nM) in vitro to form solid CLU-Aβ42 complexes. This CLU binding prevented further aggregation of Aβ42 into larger oligomers or fibrils, enriching the population of smaller Aβ42 oligomers and protofibrils and monomers. CLU either alleviated or augmented Aβ42-induced cytotoxicity and apoptosis in the neuroblastoma-derived SH-SY5Y and N2a cells, depending on the incubation period and the molar ratio of CLU:Aβ42 involved in the reaction before addition to the cells. Thus, the effects of CLU on Aβ42-induced cytotoxicity were likely determined by the extent to which it bound and sequestered toxic Aβ42 oligomers or protofibrils. These findings suggest that CLU could influence amyloid neurotoxicity and pathogenesis by modulating Aβ aggregation.

BACKGROUND: Apolipoprotein J (Apo-J) may act as a neuroprotective factor after acute brain injury. We gauged plasma Apo-J concentrations in patients with acute intracerebral hemorrhage (ICH) and investigated its predictive value for 90-day outcome and disease severity.
METHODS: This prospective cohort study included 123 ICH patients and 123 healthy controls. The severity of ICH was assessed using the Glasgow Coma Scale (GCS) score and hematoma volume. Poor outcome was referred to as a Glasgow Outcome Scale (GOS) score of 1-3 at 90 days after stroke. Multivariate analysis was performed to identify associations of plasma Apo-J concentrations with disease severity and poor outcome.
RESULTS: The plasma Apo-J concentrations of patients were significantly higher than those of healthy controls (median, 95.50 mg/l versus 55.71 mg/l; P < 0.001), and were independently correlated with hematoma volume (t = 2.716; P = 0.008) and GCS score (t = -5.978; P < 0.001). Plasma Apo-J significantly differentiated patients at risk of poor outcome (area under receiver operating characteristic curve (AUC), 0.772; 95% confidence interval (CI), 0.688-0.843; P < 0.001), and its predictive ability was similar to those of GCS score (AUC, 0.851; 95% CI, 0.776-0.909; P = 0.056) and hematoma volume (AUC, 0.849; 95% CI, 0.774-0.907, P = 0.089). Using maximum Youden index, plasma Apo-J concentrations >113.21 mg/l distinguished the development of poor outcome, with a sensitivity of 67.3% and a specificity of 87.3%. Plasma Apo-J concentrations >113.21 mg/l (odds ratio, 4.042; 95% CI, 1.093-14.951; P = 0.036) and hematoma volume (odds ratio, 1.124; 95% CI, 1.014-1.247; P = 0.027) were independently associated with poor outcome.
CONCLUSIONS: Plasma Apo-J concentrations are markedly associated with disease severity and 90-day poor outcome in ICH patients. Hence, plasma Apo-J is presumed to be used as a potential prognostic biomarker of ICH.

Affinity chromatography has, for many years, been at the research forefront as one of the simplest although highly versatile techniques capable of identifying biologically relevant protein-protein interactions. In the field of amyloid disorders, the use of ligands immobilized to a variety of affinity matrices was the method of choice to individualize proteins with affinity for soluble circulating forms of amyloid subunits. The methodology has also played an important role in the identification of proteins that interact with different amyloidogenic peptides and, as a result, are capable of modulating their physiological and pathological functions by altering solubility, aggregation propensity, and fibril formation proclivity. Along this line, classical studies conducted in the field of Alzheimer\'s disease (AD) identified clusterin as a major binding protein to both circulating soluble Aβ as well as to the brain deposited counterpart. The affinity chromatography-based approach employed herein, individualized clusterin as the major protein capable of binding the amyloid subunits associated with familial British and Danish dementias, two non-Aβ neurodegenerative conditions also exhibiting cerebral amyloid deposition and sharing striking similarities to AD. The data demonstrate that clusterin binding ability to amyloid molecules is not restricted to Aβ, suggesting a modulating effect on the aggregation/fibrillization propensity of the amyloidogenic peptides that is consistent with its known chaperone activity.

Parkinson\'s disease (PD)-a neurodegenerative disorder (NDD) characterized by progressive destruction of dopaminergic neurons within the substantia nigra of the brain-is associated with the formation of Lewy bodies containing mainly α-synuclein. HDL-related proteins such as paraoxonase 1 and apolipoproteins A1, E, D, and J are implicated in NDDs, including PD. Apolipoprotein J (ApoJ, clusterin) is a ubiquitous, multifunctional protein; besides its engagement in lipid transport, it modulates a variety of other processes such as immune system functionality and cellular death signaling. Furthermore, being an extracellular chaperone, ApoJ interacts with proteins associated with NDD pathogenesis (amyloid β, tau, and α-synuclein), thus modulating their properties. In this review, the association of clusterin with PD is delineated, with respect to its putative involvement in the pathological mechanism and its application in PD prognosis/diagnosis.