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Mapping the hippocampal spatial proteomic signature in male and female mice of an early Alzheimer's disease model.

BACKGROUND: Hippocampal dysfunction induced by soluble amyloid-β oligomers (oAβ) is an early neuropathological hallmark of Alzheimer's disease (AD). oAβ shifts hippocampal synaptic-plasticity induction threshold facilitating long-term depression (LTD) instead of long-term potentiation (LTP, the functional basis of memory), thereby leading to memory deficits in early AD-like amyloidosis mouse models. In this regard, the spatial distribution of the underlying synaptic-plasticity/memory proteome changes in the hippocampus, and potential sex differences, remain unknown. Here we postulated that som…

Real-world utilization of guideline-directed genetic testing in inherited cardiovascular diseases.

BACKGROUND: Cardiovascular disease continues to be the leading cause of death globally. Clinical practice guidelines aimed at improving disease management and positively impacting major cardiac adverse events recommend genetic testing for inherited cardiovascular conditions such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), hereditary amyloidosis, and familial hypercholesterolemia (FH); however, little is known about how consistently practitioners order genetic testing for these conditions in routine clinical practice. This study aimed to assess t…

Astrocytes & Astrocyte derived Extracellular Vesicles in Morphine Induced Amyloidopathy: Implications for Cognitive Deficits in Opiate Abusers.

While opiates like morphine play a major role in the pharmacotherapy for the control of pain associated with various diseases, paradoxically, their long-term use is associated with cognitive impairments. Furthermore, morphine administration has been shown to result in neuronal synaptodendritic injury in rodent brains, leading to neurodegeneration. We recently reported the role of astrocytes as contributors of amyloidosis associated with HIV-associated neurological disorders. Herein we hypothesize that morphine could induce astrocytic amyloidosis, which, in turn, could be disseminated to variou…

Feasibility of Hepatic T1-Mapping and Extracellular Volume Quantification on Routine Cardiac Magnetic Resonance Imaging in Patients with Infiltrative and Systemic Disorders.

RATIONALE AND OBJECTIVES: Cardiac magnetic resonance imaging (CMR) is commonly obtained to evaluate for myocardial infiltrative disorders and fibrosis. Pre- and post-Gadolinium contrast T1-mapping sequences are employed to estimate interstitial expansion using extracellular volume fraction (ECV). Given the proximity of the liver to the heart, T1 and ECV quantification of the liver is feasible on CMR. The purpose of this study was to evaluate for hepatic measures of fibrosis and interstitial expansion in patients with amyloidosis or systemic disease on CMR. MATERIALS AND METHODS: Myocardial an…

Native T1 reference values for nonischemic cardiomyopathies and populations with increased cardiovascular risk: A systematic review and meta-analysis.

BACKGROUND: Although cardiac MR and T1 mapping are increasingly used to diagnose diffuse fibrosis based cardiac diseases, studies reporting … myopathy (HCM) and dilated cardiomyopathy (DCM), and patients with myocarditis (MC), iron overload, amyloidosis, Fabry disease, and populations with hypertension (HT), diabetes mellitus (DM), and obesity. FIELD STRENGTH/SEQUENCE: (Shortened) modified Look-Locker inversion-recovery MR sequence at 1.5 or 3T. ASSESSMENT: PubMed and Embase were searched followin …

High frequency of amyloid lymphadenopathy in uremic patients.

Amyloid lymphadenopathy has only been reported in case report form, or in small groups of patient groups within large series. We believe tha … 10 patients for causes of end-stage renal disease (ESRD) and other conditions that might relate to amyloidosis. The cause of ESRD in the seven patients with AA amyloid were renal amyloidosis secondary to Familial Mediterranean Fever in four, glomerulonephritis in one patient who had bronchiectasis and Castleman's disease, unknown in one patient who had bronc …

[Monoclonal gammopathies].

Monoclonal gammopathies range from benign conditions to severe malignancies. A summary is given in this review. Overall, the prevalence is high; monoclonal gammopathies (MGUS) occur in > 3% of persons above 50 years of age. Approximately 400 new cases of multiple myeloma and 80 new cases of amyloid light-chain (AL) amyloidosis are diagnosed yearly in Denmark. MGUS is most often asymptomatic, but M-protein associated syndromes exist and should be considered when finding M-protein. Serum free light kappa and lambda chain analysis, CT, PET/CT and whole-body MRI have revolutionised diagnostics and…

Solid Organ Transplantation.

Please add expansion for AL. Hematologic disease control combined with solid organ transplantation can result in long-term survival in selected patients with light chain (AL) amyloidosis and limited other organ involvement. Restoration of critical cardiac function with organ transplantation can render patients eligible for effective disease-directed therapies, including high-dose therapy and autologous stem cell transplantation. Access to directed-donor organs, exchange programs for renal transplantation, and extended-donor organs for cardiac transplantation improves the availability of organs…

АнтиCD38 моноколональные антитела в множестве миеломы и за ее пределами: иммунотерапевтические механизмы, зрелость улик и клиническое позиционирование.

АнтиCD38 моноколональные антитела стали центральной иммунотерапевтической платформой во множестве миэломы, где они изменили курс лечения от рецидива или рефракторного заболевания, передней терапии, интенсификации технического обслуживания и минимального управления, ориентированного на остаточные заболевания. Их успех в многочисленных миеломах также стимулировал более широкое развитие в области иммуноглобулинового светового амилоида, отдельных гематологовых магнелез и юморальных иммунных расстройств. CD38 функционирует как как поверхностная мишень, так и как эктоэнзим, связанный с метаболизмом

Совпадение в аннотации оригинала
Anti-CD38 monoclonal antibodies have become a central immunotherapeutic platform in multiple myeloma, where they have reshaped treatment acr … r success in multiple myeloma has also stimulated broader development in immunoglobulin light-chain amyloidosis, selected hematologic malignancies, and humoral immune-mediated disorders. CD38 functions both as a surface target and as an ectoenzyme involved in nicotinamide adenine dinucleotide metabolism, calcium signaling, immune-cell regulation, and microenv …

International prevalence of transthyretin amyloid cardiomyopathy in high-risk patients with heart failure and preserved or mildly reduced ejection fraction.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure (HF). METHODS: This epidemiology study assessed the international prevalence of ATTR-CM among patients aged ≥60 years with a history of HF, left ventricular ejection fraction (LVEF) >40%, an end-diastolic interventricular septum thickness (IVST) ≥12 mm, but without diagnosed amyloidosis, history of LVEF ≤40%, cardiomyopathy of known cause, severe valvular, or coronary heart disease. ATTR-CM was determined using cardiac scintigraphy alongside exclusionary testing for light chain amyloidosis. …

Muckle-Wells Syndrome Across Four Generations in One Czech Family: Natural Course of the Disease.

Background: Muckle-Wells syndrome (MWS) represents a moderate phenotype of cryopyrinopathies. Sensorineural hearing loss and AA amyloidosis belong to the most severe manifestations of uncontrolled disease. Simultaneous discovery of MWS in four generations of one large kindred has enabled us to document natural evolution of untreated disease and their response to targeted therapy. Methods: A retrospective case study, clinical assessment at the time of diagnosis and 2-year prospective follow-up using standardized disease assessments were combined. Results: Collaborative effort of primary care ph…

Influence of Decreased Kidney Function on Plasma Biomarkers of Neurodegenerative Disorders in Routine Care: Confirmation of the Interest of Ratios.

BACKGROUND AND OBJECTIVES: Interest in plasma biomarkers for neurodegenerative disorders is growing, but their reliance on glomerular filtration makes kidney function a key potential confounder. This study assesses the effect of kidney function (eGFR) on plasma biomarkers of neurodegeneration and on their accuracy for detecting cerebral amyloidosis. METHODS: This observational study aims at studying the effect of kidney function on blood biomarkers through simultaneous measurements of creatinine, plasma, and CSF biomarkers (Aβ42, Aβ40, p-tau181, p-tau217, neurofilament light chain [NfL], glia…

Outcome of liver transplantation for familial amyloidotic polyneuropathy.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant disorder caused by mutation in the transthyretin gene. The most common mu … T in patients with MET30 and NMET30 mutations. Medical records of all patients who underwent LT for amyloidosis at our institution were reviewed to obtain demographic information and clinical features, such as severity of neuropathy, diarrhea, orthostatic hypotension, and posterior wall or ventricle septal thickness before and after LT. Fifteen patients under …

Recent advances in small molecules for amyloid fibril inhibition: chemical strategies and molecular mechanistic insights from lysozyme and insulin models.

Protein misfolding and aggregation are central pathological processes underlying amyloidosis, a group of disorders characterized by the deposition of insoluble amyloid fibrils. These toxic aggregates form due to conformational destabilization and exposure of hydrophobic protein regions, leading to aberrant interactions that disrupt normal cellular functions. Amyloid fibrillation is a key pathological event in both neurodegenerative and systemic disorders. In metabolic and systemic amyloidosis, such as lysozyme derived and insulin derived amyloidosis, peripheral fibril deposition leads to progr…

Cryo-EM structures of ALECT2 filaments from human renal biopsies.

Leukocyte chemotactic factor 2 is a recently identified amyloidogenic protein, whose abnormal aggregation defines a systemic amyloidosis termed ALECT2 amyloidosis. Due to the lack of reliable biomarkers, diagnosis relies primarily on histological demonstration and typing of amyloid deposits in renal biopsies. However, immunohistochemical detection of ALECT2 is often inconsistent, leading to diagnostic uncertainty. The underlying basis remains poorly understood, reflecting our limited knowledge of ALECT2 deposits. Here, using cryo-electron microscopy (cryo-EM), we determined the structures of A…

Role of Zn(II) in the aggregation of the 6aJL2R24G protein: Experimental and theoretical approach.

Light chain amyloidosis is a conformational disease, and one of the most common systemic amyloidosis. It is characterized by the deposition of amyloid aggregates of immunoglobulin light chains in organs and tissues. 6aJL2R24G is a recombinant variant of the λ6a germline protein, a germline present in 25 % of the amyloid-associated λ6a light chain amyloidosis cases. In this study, using spectroscopic and computational methodologies, we found that the interaction of this protein with Zn(II) accelerates amyloid fibril initiation and slows down elongation, without altering the fiber morphology. Al…

Suppressing transthyretin production in mice, monkeys and humans using 2nd-Generation antisense oligonucleotides.

Transthyretin amyloidosis (ATTR amyloidosis) is a rare disease that results from the deposition of misfolded transthyretin (TTR) protein from the plasma into tissues as amyloid fibrils, leading to polyneuropathy and cardiomyopathy. IONIS-TTRRx (ISIS 420915) is a 2nd-Generation 2'-O-(2-methoxyethyl) modified "2'-MOE" antisense oligonucleotide (ASO) that targets the TTR RNA transcript and reduces the levels of the TTR transcript through an RNaseH1 mechanism of action, leading to reductions in both mutant and wild-type TTR protein. The activity of IONIS-TTRRx to decrease TTR protein levels was st…

The conformational landscape of human transthyretin revealed by cryo-EM.

Transthyretin (TTR) is a natively tetrameric thyroxine transporter in blood and cerebrospinal fluid whose misfolding and aggregation causes TTR amyloidosis. A rational drug design campaign identified the small molecule tafamidis (Vyndamax) as a stabilizer of the native TTR fold, and this aggregation inhibitor is regulatory agency approved for the treatment of TTR amyloidosis. Here we used cryo-EM to investigate the conformational landscape of this 55 kDa tetramer in the absence and presence of one or two ligands, revealing inherent asymmetries in the tetrameric architecture and previously unob…

Resveratrol Derivatives Inhibit Transthyretin Fibrillization: Structural Insights into the Interactions between Resveratrol Derivatives and Transthyretin.

Hereditary ATTR amyloidosis is a disease caused by the deposition of amyloid fibrils formed by mutated transthyretin (TTR), a protein that binds to thyroid hormone in the serum, in the organs. The development of a small molecule that binds to and stabilizes TTR is a promising strategy for the treatment of ATTR amyloidosis. In the present study, we demonstrated that the resveratrol derivatives including pterostilbene available as a dietary supplement inhibit the fibrillization of V30M-TTR to the same extent as the approved drug tafamidis. Furthermore, based on a thermodynamic and X-ray crystall…

Design and Synthesis of 6-O-Phosphorylated Heparan Sulfate Oligosaccharides to Inhibit Amyloid β Aggregation.

Dysregulation of amyloidogenic proteins and their abnormal processing and deposition in tissues cause systemic and localized amyloidosis. Formation of amyloid β (Aβ) fibrils that deposit as amyloid plaques in Alzheimer's disease (AD) brains is an earliest pathological hallmark. The polysulfated heparan sulfate (HS)/heparin (HP) is one of the non-protein components of Aβ deposits that not only modulates Aβ aggregation, but also acts as a receptor for Aβ fibrils to mediate their cytotoxicity. Interfering with the interaction between HS/HP and Aβ could be a therapeutic strategy to arrest amyloido…