Extracellular Amyloid Deposits Research Articles

3,4,5-trimethoxycinnamic acid methyl ester isolated from Polygala tenuifolia enhances hippocampal LTP through PKA and calcium-permeable AMPA receptor

Alzheimer’s disease (AD) is a degenerative brain disorder characterized by progressive cognitive decline and neuronal death due to extracellular deposition of amyloid β (Aβ) and intracellular deposition of tau proteins. Recently approved antibody drugs targeting Aβ have been shown to slow the progression of the disease, but they have minimal effects on cognitive improvement. Therefore, there is a need to develop drugs with cognitive-enhancing effects that can be used in conjunction with these antibody treatments. In this study, we investigated whether Polygala tenuifolia (PT), traditionally known for its cognitive-enhancing effects, can improve synaptic plasticity and identified its active components and mechanisms. PT demonstrated a dose-dependent effect in enhancing long-term potentiation (LTP), and among its components, 3,4,5-trimethoxycinnamic acid methyl ester (TMCA) showed a similar LTP-enhancing effect. TMCA increased the phosphorylation of the GluA1 subunit of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and increased the amount of GluA1 on the synapse without affecting the amount of GluA2. Additionally, the increase in GluA1 induced by TMCA was inhibited by a PKA inhibitor. Consistent with these results, the enhancement of LTP by TMCA was inhibited by a GluA1 antagonist and a PKA inhibitor. In silico molecular docking experiments confirmed that TMCA binds to PKA. Finally, we confirmed the LTP-enhancing effect of TMCA in hippocampal slices from 5XFAD mice. These results suggest that PT and its active component, TMCA, can interact with PKA to enhance LTP, indicating the potential for improving cognitive function in AD patients

Identification of epidermal growth factor-containing fibulin-like extracellular matrix protein 1-derived amyloid deposition in a rhesus macaque

Identification of epidermal growth factor-containing fibulin-like extracellular matrix protein 1-derived amyloid deposition in a rhesus macaque

IPSC-derived blood-brain barrier modeling reveals APOE isoform-dependent interactions with amyloid beta

BackgroundThree common isoforms of the apolipoprotein E (APOE) gene - APOE2, APOE3, and APOE4 - hold varying significance in Alzheimer’s Disease (AD) risk. The APOE4 allele is the strongest known genetic risk factor for late-onset Alzheimer’s Disease (AD), and its expression has been shown to correlate with increased central nervous system (CNS) amyloid deposition and accelerated neurodegeneration. Conversely, APOE2 is associated with reduced AD risk and lower CNS amyloid burden. Recent clinical data have suggested that increased blood-brain barrier (BBB) leakage is commonly observed among AD patients and APOE4 carriers. However, it remains unclear how different APOE isoforms may impact AD-related pathologies at the BBB.MethodsTo explore potential impacts of APOE genotypes on BBB properties and BBB interactions with amyloid beta, we differentiated isogenic human induced pluripotent stem cell (iPSC) lines with different APOE genotypes into both brain microvascular endothelial cell-like cells (BMEC-like cells) and brain pericyte-like cells. We then compared the effect of different APOE isoforms on BBB-related and AD-related phenotypes. Statistical significance was determined via ANOVA with Tukey’s post hoc testing as appropriate.ResultsIsogenic BMEC-like cells with different APOE genotypes had similar trans-endothelial electrical resistance, tight junction integrity and efflux transporter gene expression. However, recombinant APOE4 protein significantly impeded the “brain-to-blood” amyloid beta 1–40 (Aβ40) transport capabilities of BMEC-like cells, suggesting a role in diminished amyloid clearance. Conversely, APOE2 increased amyloid beta 1–42 (Aβ42) transport in the model. Furthermore, we demonstrated that APOE-mediated amyloid transport by BMEC-like cells is dependent on LRP1 and p-glycoprotein pathways, mirroring in vivo findings. Pericyte-like cells exhibited similar APOE secretion levels across genotypes, yet APOE4 pericyte-like cells showed heightened extracellular amyloid deposition, while APOE2 pericyte-like cells displayed the least amyloid deposition, an observation in line with vascular pathologies in AD patients.ConclusionsWhile APOE genotype did not directly impact general BMEC or pericyte properties, APOE4 exacerbated amyloid clearance and deposition at the model BBB. Conversely, APOE2 demonstrated a potentially protective role by increasing amyloid transport and decreasing deposition. Our findings highlight that iPSC-derived BBB models can potentially capture amyloid pathologies at the BBB, motivating further development of such in vitro models in AD modeling and drug development.

Recent Advances in Medicinal Chemistry of Memantine Against Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic progressive, age-related neurodegenerative brain disorder characterized by the irreversible decline of memory and other cognitive functions. It is one of the major health threat of the 21st century, which affects around 60% of the population over the age of 60 years. The problem of this disease is even more major because the existing pharmacotherapies only provide symptomatic relief without addressing the basic factors of the disease. It is characterized by the extracellular deposition of amyloid β (Aβ) to form senile plaques, and the intracellular hyperphosphorylation of tau to form neurofibrillary tangles (NFTs). Due to the complex pathophysiology of this disease, various hypotheseshave been proposed, including the cholinergic, Aβ, tau, oxidative stress, and the metal-ion hypothesis. Among these, the cholinergic and Aβ hypotheses are the primary targets for addressing AD. Therefore, continuous advances have been made in developing potential cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists to delay disease progression and restore cholinergic neurotransmission. In this review article, we tried to comprehensively summarize the recent advancement in NMDA receptor antagonist (memantine) and their hybrid analogs as potential disease-modifying agents for the treatment of AD. Furthermore, we also depicted the design, rationale, and SAR analysis of the memantine-based hybrids used in the last decade for the treatment of AD.

Alzheimer's Disease as a Membrane Dysfunction Tauopathy? New Insights into the Amyloid Cascade Hypothesis.

The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42.

Mechanisms of damage and therapies for cardiac amyloidosis: a role for inflammation?

The term cardiac amyloidosis (CA) refers to the accumulation of extracellular amyloid deposits in the heart because of different conditions often affecting multiple organs including brain, kidney and liver. Notably, cardiac involvement significantly impacts prognosis of amyloidosis, with cardiac biomarkers playing a pivotal role in prognostic stratification. Therapeutic management poses a challenge due to limited response to conventional heart failure therapies, necessitating targeted approaches aimed at preventing, halting or reversing amyloid deposition. Mechanisms underlying organ damage in CA are multifactorial, involving proteotoxicity, oxidative stress, and mechanical interference. While the role of inflammation in CA remains incompletely understood, emerging evidence suggests its potential contribution to disease progression as well as its utility as a therapeutic target. This review reports on the cardiac involvement in systemic amyloidosis, its prognostic role and how to assess it. Current and emerging therapies will be critically discussed underscoring the need for further efforts aiming at elucidating CA pathophysiology. The emerging evidence suggesting the contribution of inflammation to disease progression and its prognostic role will also be reviewed possibly offering insights into novel therapeutic avenues for CA.

Assessing left atrial dysfunction in cardiac amyloidosis using LA-LV strain slope.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an infiltrative disease of the myocardium in which extracellular deposits of amyloid cause progressive cardiac impairment. We aimed to evaluate left atrial (LA) deformation and its association with left ventricular (LV) deformation using LA-LV strain loops in patients with ATTR-CM and patients with LV hypertrophy (LVH). We hypothesized that LA strain in ATTR-CM patients is abnormal and more independent of LV strain, compared to LVH patients. Retrospective study based on echocardiographic data including 30 patients diagnosed with ATTR-CM based on an end-diastolic interventricular septal (IVSd) thickness of ≥14 mm, and 29 patients with LVH (IVSd ≥ 14 mm and no ATTR-CM diagnosis) together with 30 controls. LV global longitudinal strain (LV-GLS) and LA strain, assessed as peak atrial longitudinal strain (PALS), were acquired and plotted to construct LA-LV strain loops and used regression line to determine a LA-LV strain slope. Significantly lower PALS and LA-LV strain slope values were detected in ATTR-CM patients compared to LVH patients (P = 0.004 and P = 0.014, respectively). A receiver operating characteristic (ROC) curve demonstrated similar area under the curve (AUC) using PALS (AUC 0.72) and LA-LV slope (AUC 0.71), with both resulting in higher values than recorded for LV-GLS (AUC 0.62). LA deformation demonstrates an independent ability to differentiate ATTR-CM from LVH. Combining LV strain and LA deformation analysis displays the mechanical LA-LV dissociation in ATTR cardiac amyloidosis and potentially unmasks LA amyloid infiltration; this could potentially enable quicker diagnosis and initiation of treatment for ATTR-CM.

Pathological Defects in a Drosophila Model of Alzheimer's Disease and Beneficial Effects of the Natural Product Lisosan G.

Alzheimer's disease (AD) brains are histologically marked by the presence of intracellular and extracellular amyloid deposits, which characterize the onset of the disease pathogenesis. Increasing evidence suggests that certain nutrients exert a direct or indirect effect on amyloid β (Aβ)-peptide production and accumulation and, consequently, on AD pathogenesis. We exploited the fruit fly Drosophila melanogaster model of AD to evaluate in vivo the beneficial properties of Lisosan G, a fermented powder obtained from organic whole grains, on the intracellular Aβ-42 peptide accumulation and related pathological phenotypes of AD. Our data showed that the Lisosan G-enriched diet attenuates the production of neurotoxic Aβ peptides in fly brains and reduces neuronal apoptosis. Notably, Lisosan G exerted anti-oxidant effects, lowering brain levels of reactive oxygen species and enhancing mitochondrial activity. These aspects paralleled the increase in autophagy turnover and the inhibition of nucleolar stress. Our results give support to the use of the Drosophila model not only to investigate the molecular genetic bases of neurodegenerative disease but also to rapidly and reliably test the efficiency of potential therapeutic agents and diet regimens.

Four-dimensional computed tomography is useful for detection of apical sparing of cardiac amyloidosis.

A 73-year-old male was admitted because of recurrent syncope. He was diagnosed with transient bradycardia caused by a 2:1 atrioventricular block, and he underwent cardiac computed tomography (CT) using 320 detector-row CT to screen for coronary artery disease. Significant coronary artery stenosis was not detected, but diffuse late iodinate enhancement was found on the epi-myocardium and endo-myocardium of the interventricular septum, and endo-myocardium of the anterior and lateral left ventricular (LV) myocardium (LVM) on CT. The ejection fraction and global longitudinal strain (LS) of LVM were 53.97% and - 9.87% on CT. Apical sparing was present, meaning the LS of LV apical segments were preserved compared with basal segments on CT. Pathological findings of LVM demonstrated loss of myocardial cells and extra-cellular amyloid deposition on the direct fast scarlet staining. He was finally diagnosed with transthyretin amyloidosis.

Novel ligand conjugated poly(propylene imine) dendrimers for brain targeted delivery of tacrine hydrochloride

Alzheimer's disease (AD) is the most common type of neurodegenerative disorder characterized by extracellular deposition of Amyloid β and intracellular deposition of neurofibrillary tangles. One of the most common etiological factors is rapid and excessive hydrolysis of acetylcholine by acetylcholinesterase (AChE) enzyme. Tacrine is one of the most potent and first USFDA approved centrally acting AChE inhibitor recommended for treatment of AD, but it is no longer in use as it causes severe peripheral side effects, mainly hepatotoxicity. In this research work, novel dendrimeric conjugates were developed with an aim of enhancing the brain targeting efficiency of tacrine and eliminating the peripheral side effects. Poly(propyleneimine) G5.0 dendrimers were conjugated with oleic acid as a brain targeting ligand, and the conjugation was confirmed by Fourier-transform infrared spectroscopy, 1H nuclear magnetic resonance spectroscopy and dynamic light scattering studies. Tacrine hydrochloride was loaded into the plain dendrimer as well as oleic acid conjugated dendrimer by physical encapsulation method. The in vitro AChE inhibitory study showed retention of the AChE inhibition ability of tacrine in dendrimeric conjugates. The safety of the drug loaded conjugates was confirmed by haemolytic, nasal ciliotoxicity and cytotoxicity studies. Further, cellular uptake studies in SH-SY5Y cells showed abundance of green cytoplasmic fluorescence, suggesting enhanced internalization of dendrimeric conjugates. The results of this research work support the further exploration of this novel dendrimers based conjugated delivery system for in vivo studies as a potential alternative to treat AD.

Amyloid Protein in AL-Amyloidosis. Natural History and Potential for Regression

Amyloid light chain amyloidosis is the most commonly seen form of systemic amyloidosis and is characterized by the accumulation of circulating monoclonal immunoglobulin light chain precursors arising from an abnormal clone of plasma cells. These light chain precursors demonstrate a propensity for misfolding, aggregation and deposition as highly stable fibrillar cross-linked beta sheets in various tissues and organs in a manner characteristic of other forms of systemic amyloidosis. There have been great advances in the treatment of the underlying plasma cell dyscrasia with improved long-term survival but the persistence of extracellular amyloid deposits in the tissues of vital organs, particularly the heart and kidney remains a significant cause of morbidity and mortality even in those patients in whom a hematological complete response has been achieved. This review focuses on the importance of early diagnosis and treatment on limiting the extent of amyloid protein accumulation and organ dysfunction and the current state of knowledge on the potential for resorption and clearance of these amyloid deposits in patients with amyloid light chain amyloidosis. The status of current novel anti-fibrillar agents is reviewed and future strategies for effectively intervening to improve organ function and survival these individuals is discussed.

Amyloid PET imaging

Extracellular amyloid deposition in brain tissue is a hallmark of Alzheimer’s disease. Despite being the most common neurodegenerative disorder, it poses a major diagnostic challenge due to the lack of disease-specific biomarkers. Additionally, plaque-forming amyloid deposits are not unique to Alzheimer’s disease, but are also present in a high proportion of the elderly, as well as in patients with other neurodegenerative conditions such as dementia with Lewy bodies. Histopathological examination is the only reliable method for diagnosing the disease, but it is practically impossible to perform in vivo. Since Alzheimer’s disease is a disorder that develops asymptomatically over many years and eventually leads to severe dementia, new insights into the risk factors and markers of disease progression in the preclinical stage of the disease are needed. A better understanding of the underlying pathology is essential for the development of new therapies. In the past, this understanding came mainly from pathological studies. Positron emission tomography (PET) imaging detects the presence and activity of pathophysiological processes in vivo. By targeting different biological pathways, PET elucidates the metabolic activity of the processes that drive disease progression. Ongoing studies aim to clarify whether amyloid PET imaging can also be useful in assessing treatment response. In this review, recent advances in amyloid PET imaging that have significantly improved our understanding of the pathological basis of this disease are discussed.

Alzheimer's disease, a metabolic disorder: Clinical advances and basic model studies (Review).

Alzheimer's disease (AD) is a type of neurodegenerative disease characterized by cognitive impairment that is aggravated with age. The pathological manifestations include extracellular amyloid deposition, intracellular neurofibrillary tangles and loss of neurons. As the world population ages, the incidence of AD continues to increase, not only posing a significant threat to the well-being and health of individuals but also bringing a heavy burden to the social economy. There is epidemiological evidence suggesting a link between AD and metabolic diseases, which share pathological similarities. This potential link would deserve further consideration; however, the pathogenesis and therapeutic efficacy of AD remain to be further explored. The complex pathogenesis and pathological changes of AD pose a great challenge to the choice of experimental animal models. To understand the role of metabolic diseases in the development of AD and the potential use of drugs for metabolic diseases, the present article reviews the research progress of the comorbidity of AD with diabetes, obesity and hypercholesterolemia, and summarizes the different roles of animal models in the study of AD to provide references for researchers.

Conformational Properties of Aβ Peptide Oligomers in Aqueous Ionic Liquid Solution: Insights from Molecular Simulation Studies.

Alzheimer's disease is a progressive irreversible neurological disorder with abnormal extracellular deposition of amyloid β (Aβ) peptides in the brain. We have carried out atomistic molecular dynamics simulations to investigate the size-dependent conformational properties of aggregated Aβ oligomers of different orders, namely, pentamer [O(5)], decamer [O(10)], and hexadecamer [O(16)] in aqueous solutions containing the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM][BF4]). The calculations revealed reduced peptide conformational fluctuations in O(5) and O(10) in the presence of the IL. In contrast, the higher order oligomer [O(16)] has been found to exhibit greater structural distortion due to enhanced flexibilities of its peptide units in the presence of the IL. Based on the distributions of the solvent (water) and the cosolvent (IL) components, it is demonstrated that exchange of water by the IL ion pairs at the exterior surface of the oligomers primarily occurs beyond the first layer of surface-bound water molecules. Importantly, a reduced number of relatively weaker peptide salt bridges have been found in O(16) in binary water-IL solution as compared to the other two smaller-sized oligomers [O(5) and O(10)]. Such differential influence of the IL on peptide salt bridges results in less favorable binding free energies of peptide monomers to O(16), which leads to its greater structural distortion and reduced stability compared to those of O(5) and O(10).

In vivo nanotracer for the detection of brain thrombi in an AD mouse model.

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia (1). It is a multifactorial degenerative disease pathologically characterized by intracellular neurofibrillary tangles and extracellular deposition of amyloid. An early haemostatic dysregulation is also present and contributes to an increment in clot formation, leading to hypoperfusion, blood brain barrier disruption and neuronal loss (2). The detection of this prothrombotic state is of the upmost importance in diagnostic approaches to identify AD patients who would benefit from anticoagulation.AimUsing the in vivo nanotracer Thrombo‐tag (3) for the detection of brain thrombi in an AD mouse model by fast pre‐targeted positron emission tomography (PET) imaging.MethodAD animals and their wild‐type (WT) littermates were intravenously injected with the antiplatelet antibody against CD41 conjugated with transcyclooctene (TCO‐antiCD41). Twenty‐four hours later, [68Ga]core‐doped iron oxide nanoparticles (NP) functionalized with tetrazine (TZ) were intravenously administered. TCO and TZ produce a rapid in vivo reaction by means of bioorthogonal chemistry, allowing to non‐invasively evaluate platelets’ levels by PET. Two hours after [68Ga]NP‐TZ injection, a static PET study of each mouse was acquired with a scanner for small animals (nanoScan® PET/CT, Mediso, USA). Finally, biodistribution assays of different organs after the PET study were performed. All PET images were analyze by regions of interest (ROI) and voxel‐wise analyses.ResultThrombo‐tag has proven to be an effective and efficient method for neuroimaging in vivo. This PET probe allows us to accurately identify the presence and accumulation of platelets within the brain of animal models of Alzheimer’s disease. Additionally, Thrombo‐tag enables us to determine the distribution of platelets’ accumulations within various regions of the brain in comparison to WT controls.ConclusionThrombo‐tag provides a neuroimaging biomarker that could allow us to diagnose the prothrombotic state towards the personalization of anticoagulation treatment in AD patients.Funding: Carlos is the recipient of a Predoctoral Fellowship from the Fundación Española de Trombosis y Hemostasia.Bibliography: 1. Alzheimers Dement, 17, 327‐406, (2021), doi.org/10.1002/alz.123282. Cortes‐Canteli & Iadecola, Journal of the American College of Cardiology, 75, 942‐951, (2020)3. Adrover, Pellico et al., Nanoscale, 12, 22978‐22987, (2020)

INPP5D is associated with tau seeding and tau pathogenesis

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia characterized by extracellular amyloid deposits and intracellular neurofibrillary tangles composed of hyperphosphorylated tau aggregates. GWAS studies have identified variants in several inflammatory genes as significant risk factors for AD, highlighting that neuroinflammation is a critical, underlying pathological component in AD. INPP5D, a family member of Src homology 2 domain containing inositol 5' polyphosphatases (SHIPs), is an AD risk gene related to innate immunity in late‐onset AD (LOAD). Inpp5d plays a role in regulating signal transduction initiated by immune cell surface receptors. INPP5D binds receptor ITIMs, competes with kinases, and converts PI(3,4,5)P3 to PI(3,4)P¬2, thereby limiting downstream signaling. We previously reported that Inpp5d expression is increased in LOAD and is positively correlated with amyloid burden. However, the relationship of Inpp5d in tau pathology remains unclear. We hypothesize that inhibiting INPP5D will release the break and increase microglial function.MethodsTo assess the role of Inpp5d in tau pathology, we performed a fluorescence resonance energy transfer (FRET) assay on human‐AD brains obtained from NCRAD. We also crossed a mouse model deficient in Inpp5d (Inpp5d+/−) with a PS19 model of tau pathology and measured tau phosphorylation and transcriptomics. Primary microglia were utilized to measure microglial internalization of Tau.ResultsIn human AD‐ brains, increased tau seeding was positively correlated with Inpp5d expression. Furthermore, in PS19 mice, Inpp5d protein expression was upregulated and positively correlated with phosphorylated tau (S202, Thr205). Utilizing the NanoString nCounter assay, we found an upregulation of the immune‐related and cell migration related genes in PS19.Inpp5d+/‐ mice compared to PS19 mice. Primary microglia from Inpp5d+/− mice released increased tau internalization compared to WT microglia.ConclusionOur findings confirmed that elevated Inpp5d expression in human‐AD subjects is recapitulated in PS19 mice and correlated with increased tau pathology. In PS19.Inpp5d+/‐ mice we found alterations in immune related and cell migration related pathways suggesting that Inpp5d modulates the disease progression through these pathways. Furthermore, pathogenesis may be modulated through increased internalization of tau. Together these results suggest that therapeutic interventions aimed at reducing Inpp5d may be beneficial in tauopathies.

Modeling neuropathology of Alzheimer’s disease in aged patient‐derived neurons through 3D direct neuronal reprogramming

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of adult‐onset neurodegenerative diseases characterized by three hallmarks of neuropathology including the extracellular deposition of amyloid β (Aβ), intracellular tau tangles, and neurodegeneration. The mechanisms that underlying the late‐onset AD (LOAD), the most common form of AD, remain largely unresolved due to the complexity of risk factors underlying the disease. Currently, endogenously recapitulating these events in patients‐derived neurons remains a major challenge, limiting our ability to understand the biology of the disease.MethodBy optimizing the potency of microRNA‐mediated direct neuronal conversion of patient fibroblasts, we developed a matrigel‐based three‐dimensional (3D) culture system for generating cortical neurons, a subtype known to be susceptible to develop AD pathologies. For characterizing AD‐associated phenotypes such as amyloid β(Aβ) plaques, tau pathology, and neurodegeneration in the reprogrammed cortical neurons, we carried out immunofluorescence staining, RNA‐sequencing and other biochemistry‐based assays.ResultsThe 3D reprogrammed neurons derived from familial AD and LOAD patients endogenously displayed all three AD hallmark pathologies, including increased extracellular Aβ deposition, phosphorylated tau, dystrophic (beaded) neurites characterized by the colocalization between Ubquitin‐K63 and pTAU, as well as spontaneous neuronal cell death in culture without additional cellular insult. By using this 3D reprograming model, we found that treating AD neurons with β or γ secretase inhibitors at pre‐Aβ aggregation phase, significantly ameliorated Aβ formation and subsequent tauopathy and neuronal cell death, whereas treating during the post‐Aβ aggregation phase only had a mild effect. Additionally, comparative transcriptomic analysis between AD neurons and age‐matched healthy control neurons showed enrichment of genes involved in inflammatory pathways.ConclusionWe established a novel patient derived neuronal 3D direct reprogramming model which robustly recapitulates key AD hallmarks including the extracellular deposition of Aβ plaques, formation of intracellular Tau tangles, and neurodegeneration. By using this 3D platform, we further demonstrated that inhibition of Amyloid β formation reduces tauopathy and neuronal cell death. Our unique patient specific 3D model system provides opportunities to investigate the interplay between AD pathological events and could serve as a platform for screening compounds and developing personalized therapeutics for AD.

Disease spectrum of myopathies with elevated aldolase and normal creatine kinase.

Elevation of serum creatine kinase (CK) or hyperCKemia is considered a biological marker of myopathies. However, selective elevation of serum aldolase with normal CK has been reported in a few myopathies, including dermatomyositis, immune-mediated myopathy with perimysial pathology and fasciitis with associated myopathy. The aim was to investigate the disease spectrum of myopathies with isolated aldolase elevation. Medical records were reviewed to identify patients >18 years old seen between December 1994 and June 2020 who had pathologically proven myopathies with elevated aldolase and normal CK level. Patients with alternative causes of aldolase elevation were excluded. Thirty-four patients with various types of myopathies were identified. Myopathies were treatable in 27 patients. The three most common etiologies were dermatomyositis (n = 8), overlap myositis (n = 4) and nonspecific myopathy (n = 4). Perimysial pathology comprising inflammation, fragmentation, vasculitis, calcified perimysial vessels or extracellular amyloid deposition was found in 17/34 patients (50%). Eight dermatomyositis patients with selective elevated aldolase were compared to 24 sex- and age-matched patients with dermatomyositis and hyperCKemia. Dermatomyositis patients with normal CK significantly (p < 0.05) had less frequent cutaneous involvement (50.0% vs. 100.0%) and fibrillation potentials (50.0% vs. 90.5%) but higher median erythrocyte sedimentation rate (33.5 vs. 13.5 mm/h) and more common perifascicular mitochondrial pathology (37.5% vs. 4.2%). Isolated aldolase elevation can be found in a greater variety of myopathies than initially thought and most were treatable. Dermatomyositis is the most common myopathy with selective elevation of aldolase in our cohort, which features some unique characteristics compared to dermatomyositis with hyperCKemia.

Nascent Aβ42 Fibrillization in Synaptic Endosomes Precedes Plaque Formation in a Mouse Model of Alzheimer's-like β-Amyloidosis.

Accumulation of amyloid-β peptide (Aβ) aggregates in synapses may contribute to the profound synaptic loss characteristic of Alzheimer's disease (AD). The origin of synaptic Aβ aggregates remains elusive, but loss of endosomal proteostasis may trigger their formation. In this study, we identified the synaptic compartments where Aβ accumulates, and performed a longitudinal analysis of synaptosomes isolated from brains of TgCRND8 APP transgenic mice of either sex. To evaluate the specific contribution of Aβ-degrading protease endothelin-converting enzyme (ECE-1) to synaptic/endosomal Aβ homeostasis, we analyzed the effect of partial Ece1 KO in brain and complete ECE1 KO in SH-SY5Y cells. Global inhibition of ECE family members was used to further assess their role in preventing synaptic Aβ accumulation. Results showed that, before extracellular amyloid deposition, synapses were burdened with detergent-soluble Aβ monomers, oligomers, and fibrils. Levels of all soluble Aβ species declined thereafter, as Aβ42 turned progressively insoluble and accumulated in Aβ-producing synaptic endosomal vesicles with characteristics of multivesicular bodies. Accordingly, fibrillar Aβ was detected in brain exosomes. ECE-1-deficient mice had significantly increased endogenous synaptosomal Aβ42 levels, and protease inhibitor experiments showed that, in TgCRND8 mice, synaptic Aβ42 became nearly resistant to degradation by ECE-related proteases. Our study supports that Aβ accumulating in synapses is produced locally, within endosomes, and does not require the presence of amyloid plaques. ECE-1 is a determinant factor controlling the accumulation and fibrillization of nascent Aβ in endosomes and, in TgCRND8 mice, Aβ overproduction causes rapid loss of Aβ42 solubility that curtails ECE-mediated degradation.SIGNIFICANCE STATEMENT Deposition of aggregated Aβ in extracellular plaques is a defining feature of AD. Aβ aggregates also accumulate in synapses and may contribute to the profound synaptic loss and cognitive dysfunction typical of the disease. However, it is not clear whether synaptotoxic Aβ is mainly derived from plaques or if it is produced and aggregated locally, within affected synaptic compartments. Filling this knowledge gap is important for the development of an effective treatment for AD, as extracellular and intrasynaptic pools of Aβ may not be equally modulated by immunotherapies or other therapeutic approaches. In this manuscript, we provide evidence that Aβ aggregates building up in synapses are formed locally, within synaptic endosomes, because of disruptions in nascent Aβ proteostasis.

Localized amyloidosis of the ureter: a case report

BackgroundAmyloidosis is a collection of disorders characterized by the extracellular deposition of amyloid, a specialized fibrous protein, in diverse tissues, leading to functional impairments.Case presentationA 70-year old Asian-Japanese female was referred to our department for further examination of her left hydronephrosis come from lower ureteral obstruction. Contrast enhanced CT and retrograde pyelo-nephrography revealed left ureteral tumor. Though ureteroscropic biopsy did not show malignant pathological findings, ureteroscopic image suspected malignant disease, thus nephroureterectomy was performed. Pathological findings revealed localized ureteral amyloidosis. Whole body examination including gastro endoscopy and cardio ultrasonography could not reveal amyloidosis except ureter. She was free from recurrence 9 months postoperatively.ConclusionWe herein report a rare case of localized ureteral amyloidosis.