The aggregation of amyloid beta (Aβ) is a hallmark of Alzheimer's disease (AD), a major cause of dementia and an unmet challenge in modern medicine. In this study, we constructed a biocompatible metal-phenolic network (MPN) comprising a polyphenol epigallocatechin gallate (EGCG) scaffold coordinated by physiological Zn(II). Upon adsorption onto gold nanoparticles, the MPN@AuNP nanoconstruct elicited a remarkable potency against the amyloid aggregation and toxicity of Aβ in vitro. The superior performance of MPN@AuNP over EGCG@AuNP was attributed to the porosity and hence larger surface area of the MPN in comparison with that of EGCG alone. The atomic detail of Zn(II)-EGCG coordination was unraveled by density functional theory calculations and the structure and dynamics of Aβ aggregation modulated by the MPN were further examined by discrete molecular dynamics simulations. As MPN@AuNP also displayed a robust capacity to cross a blood-brain barrier model through the paracellular pathway, and given the EGCG's function as an anti-amyloidosis and antioxidation agent, this MPN-based strategy may find application in regulating the broad AD pathology beyond protein aggregation inhibition.

B-cell maturation antigen (BCMA) is the lead antigen for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). A challenge is inter- and intra-patient heterogeneity in BCMA expression on MM cells and BCMA downmodulation under therapeutic pressure. Accordingly, there is a desire to augment and sustain BCMA expression on MM cells in patients that receive BCMA-CAR T-cell therapy. We used all-trans retinoic acid (ATRA) to augment BCMA expression on MM cells and to increase the efficacy of BCMA-CAR T cells in pre-clinical models. We show that ATRA treatment leads to an increase in BCMA transcripts by quantitative reverse transcription polymerase chain reaction and an increase in BCMA protein expression by flow cytometry in MM cell lines and primary MM cells. Analyses with super-resolution microscopy confirmed increased BCMA protein expression and revealed an even distribution of non-clustered BCMA molecules on the MM cell membrane after ATRA treatment. The enhanced BCMA expression on MM cells after ATRA treatment led to enhanced cytolysis, cytokine secretion and proliferation of BCMA-CAR T cells in vitro, and increased efficacy of BCMA-CAR T-cell therapy in a murine xenograft model of MM in vivo (NSG/MM.1S). Combination treatment of MM cells with ATRA and the γ- secretase inhibitor crenigacestat further enhanced BCMA expression and the efficacy of BCMA-CAR T-cell therapy in vitro and in vivo. Taken together, the data show that ATRA treatment leads to enhanced BCMA expression on MM cells and consecutively, enhanced reactivity of BCMA-CAR T cells. The data support the clinical evaluation of ATRA in combination with BCMA-CAR T-cell therapy and potentially, other BCMA-directed immunotherapies.

Patient-reported outcomes in AL amyloidosis have not been well studied. We analyzed health-related quality of life (HRQOL) and AL amyloidosis symptoms data from the phase 3 TOURMALINE-AL1 trial (NCT01659658) (ixazomib-dexamethasone, n=85; physician's choice of chemotherapy [PC], n=83). HRQOL and symptom burden were measured with the SF-36v2, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity subscale (FACT/GOG-Ntx), and an amyloidosis symptom questionnaire (ASQ). Score changes during treatment were analyzed descriptively and using repeated-measures linear mixed models; analyses were not adjusted for multiplicity. Least-squares (LS) mean changes from baseline were significantly higher (better HRQOL) for ixazomib-dexamethasone at several cycles for SF-36v2 Role Physical and Vitality subscales (P<0.05); no subscales demonstrated significant differences favoring PC. For FACT/GOG-Ntx, small but significant differences in LS mean changes favored ixazomib-dexamethasone over PC at multiple cycles for 7 items and both summary scores; significant differences favored PC for 1 item (trouble hearing) at multiple cycles. ASQ total score trended downward (lower burden) in both arms; significant LS mean differences favored ixazomib-dexamethasone over PC at some cycles (P<0.05). Patients with relapsed/refractory AL amyloidosis treated with ixazomib-dexamethasone experienced HRQOL and symptoms that were similar to or trended better than patients treated with PC despite longer duration of therapy. This article is protected by copyright. All rights reserved.

BACKGROUND Amyloid light-chain (AL) amyloidosis is usually due to deposition of immunoglobulin lambda light chains from plasma cells in patients with multiple myeloma. AL amyloid may involve the salivary glands, gastrointestinal tract, peripheral nerves, and skin. However, musculoskeletal amyloid and amyloid arthropathy are rare. This report is of a woman with bilateral upper limb musculoskeletal amyloid and amyloid arthropathy associated with multiple myeloma, initially diagnosed and managed as a case of rheumatoid arthritis. CASE REPORT A 59-year-old woman who was initially diagnosed with rheumatoid arthritis presented with bilateral polyarthritis in the upper limbs. Despite treatment with corticosteroids, methotrexate, and hydroxychloroquine, her symptoms did not improve. After 4 months, she revisited our hospital with the appearance of swollen soft tissue in the upper right arm and numbness of the right hand. She had an arthroscopic synovectomy of the right shoulder joint, and the mass in the right elbow area was removed. These specimens were positive by Congo red stain and confirmed the deposition of light chain protein as amyloid. She was diagnosed with multiple myeloma according to International Myeloma Working Group criteria, including bone marrow plasma cells more the 10%, lytic lesions in bone, and anemia. CONCLUSIONS This report highlights the importance of imaging, biopsy, and laboratory investigations in patients with arthropathy and musculoskeletal disease. In this case, the patient was seronegative for rheumatoid arthritis, and the presentation with very thick and nodular synovium supported an alternative diagnosis. The identification of musculoskeletal amyloid and amyloid arthropathy confirmed underlying multiple myeloma.

Systemic light-chain (AL) amyloidosis is a rare and debilitating disease. Advances have been made in new treatments in recent years, yet real-world data on the management of the disease are scarce. EMN23 is a retrospective, observational study of patients who initiated first-line treatment in 2004-2018 in Europe, presenting the demographics, clinical characteristics, treatment patterns, and outcomes, from 4480 patients. Regimens based on bortezomib were the most frequently used as first-line therapy; only 6.2% of the patients received autologous stem cell transplant. Hematologic responses improved post-2010 (67.1% vs 55.6% pre-2010). The median overall survival (OS) was 48.8 (45.2-51.7) months; 51.4 (47.3-57.7) months pre-2010 and 46.7 (41.3-52.2) months post-2010. Early mortality was 13.4% and did not improve (11.4% vs 14.4% pre- and post-2010); furthermore, it remained high in patients with advanced cardiac disease (over 39% for stage IIIb). There was a significant improvement for stage IIIa (14.2 vs 30.7 months, p = 0.0170) but no improvement for stage IIIb patients (5.0 vs 4.5 months). This European real-world study of AL-amyloidosis emphasizes the unmet needs of early diagnosis, and the lack of improvement in survival outcomes of the frail stage IIIb population, despite the introduction of new therapies in recent years.

Light-chain (AL) amyloidosis is a type of plasma cell neoplasm with abnormal monoclonal immunoglobulin light-chain production and their subsequent deposition in tissues causing end-organ damage. In addition to existing treatments including autologous stem cell transplantation, there is a need for other approaches for eradicating abnormal plasma cells and amyloid tissue deposits. Treatment strategies of AL amyloidosis are mostly based on medications that are effective in multiple myeloma due to similar cell of origin. Daratumumab along with proteasome inhibitors and corticosteroids has become standard of care for AL amyloidosis. Another appealing approach is disassembling amyloid deposits with hope to potentially reverse the damage done by the disease. This was met with promising results for CAEL-101 and birtamimab. Although still in early stages, novel treatment options in pipeline, including antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen receptor T cell therapy may diversify the treatment armamentarium of AL amyloidosis in the future.

Amyloidosis is a complex multisystem disorder characterized by deposition of an aberrant protein in tissues and results in disruption of the normal organ function. Localized amyloidosis is a rare disorder. It commonly affects the head-and-neck region, and only 4% of these lesions are encountered in the orbital region. Hence, conjunctival amyloidosis is a very rare entity. It is thought to be a manifestation of local immunologic disorders. Amyloidosis of conjunctiva is more often localized with no other systemic features. Here, we present two cases of unilateral conjunctival amyloidosis, one with extensive calcification. Conjunctival amyloidosis must be considered in the differential diagnosis of conjunctival neoplasms. Histopathological examination and apple-green birefringence on polarized microscopy with Congo red stain remain the gold standard for diagnosing this entity.

This research is relevant, as AL-amyloidosis refers to a systemic type of disease characterised by aggregation of an improperly folded light chain of immunoglobulin, mainly in the heart and kidneys, causing organ failure. This study describes the clinical experience of introducing a patient with cardiac amyloidosis associated with multiple myeloma. A clinical case of a patient diagnosed with amyloidosis was considered. MRI signs of cardiac amyloidosis were confirmed due to the presence of concentric biventricular hypertrophy without dilation, atrial septal hypertrophy, a tendency to atrial dilation, thickening of valve flaps and atrial walls. Upon admission to the research institute, the patient had an anasarca. More accurate recognition of AL-amyloidosis by cardiologists allows prescribing earlier treatment and improving results. Conventional treatment of multiple myeloma and AL-amyloidosis includes a combination of dexamethasone with bortezomib and endoxan. Hematopoietic stem cell transplantation after taking high doses of melphalan has become another treatment option and has led to remission in some patients. The novelty of the study is that an example of a timely complete diagnosis and treatment of a combination of these two diseases was presented, as a result of which the patient has achieved a complete haematological and partial organ response to the underlying disease.

Amyloidosis is a rare protein misfolding disease caused by the accumulation of amyloid fibrils in various tissues and organs. There are different subtypes of amyloidosis, with light chain (AL) amyloidosis being the most common. Amyloidosis is notoriously difficult to diagnose because it is clinically heterogeneous, no single test is diagnostic for the disease, and diagnosis typically involves multiple specialists. Here, we propose an integrated, multidisciplinary algorithm for efficiently diagnosing amyloidosis. Drawing on research from several medical disciplines, we have combined clinical decisions and best practices into a comprehensive algorithm to facilitate the early detection of amyloidosis. Currently, many patients are diagnosed more than 6 months after symptom onset, yet early diagnosis is the major predictor of survival. Our algorithm aims to shorten the time to diagnosis with efficient sequencing of tests and minimizing uninformative investigations. We also recommend typing and staging of confirmed amyloidosis to guide treatment. By reducing time to diagnosis, our algorithm could lead to earlier and more targeted treatment, ultimately improving prognosis and survival.

Primary systemic light chain amyloidosis (SLCA) is characterized by production of light chains that get converted to amyloid fibrils with an affinity for visceral organs and causing organ dysfunction. The therapy for SLCA is directed to recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of amyloid fibrils. The NCCN Guidelines for SLCA provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated SLCA.

Amyloidosis cutis dyschromica is a rare variant of primary cutaneous amyloidosis characterized by hyper- and hypopigmented macules. In this paper, we reported a case of a 16-year-old Filipino girl with hyper- and hypopigmented to depigmented macules on the upper and lower extremities, which started when she was 9 years of age.

Neuronal hyperactivity induces memory deficits in Alzheimer's disease. However, how hyperactivity disrupts memory is unclear. Using in vivo synaptic imaging in the mouse visual cortex, we show that structural excitatory-inhibitory synapse imbalance in the apical dendrites favors hyperactivity in early amyloidosis. Consistent with this, natural images elicit neuronal hyperactivity in these mice. Compensatory changes that maintain activity homeostasis disrupt functional connectivity and increase population sparseness such that a small fraction of neurons dominates population activity. These properties reduce the selectivity of neural response to natural images and render visual recognition memory vulnerable to interference. Deprivation of non-specific visual experiences improves the neural representation and behavioral expression of visual familiarity. In contrast, in non-pathological conditions, deprivation of non-specific visual experiences induces disinhibition, increases excitability, and disrupts visual familiarity. We show that disrupted familiarity occurs when the fraction of high-responsive neurons and the persistence of neural representation of a memory-associated stimulus are not constrained.

Light chain (AL) amyloidosis is a lethal form of systemic amyloidosis that arises from the clonal expansion of CD38+ plasma cells. Organ damage occurs when these plasma cells produce misfolded immunoglobulin light chains, which form amyloid fibrils and deposit in tissues. A minority of patients with AL amyloidosis show "raccoon eyes" caused by increased vascular fragility from accumulation of amyloid fibrils. Amyloidosis can be directly associated with bleeding diathesis due to factor X deficiency as factor X binds to amyloid fibrils primarily in the liver and spleen. A 65-year-old Caucasian male presented with random bruising in the upper chest and around the eyes for 1.5 years. Physical examination was unremarkable, except for neck bruising. Pertinent workup showed protein electrophoresis with a faint M spike, increased serum lambda light chains, a kappa to lambda ratio of 0.06, increased Bence-Jones proteins, reduced factor X activity, elevated NT-proBNP. The bone marrow biopsy was positive for Congo red stain for amyloid protein. Magnetic resonance imaging revealed diffuse enhancement of the right and left ventricle subendocardial late gadolinium, consistent with cardiac amyloidosis. The patient started systemic therapy with a regimen of daratumumab, cyclophosphamide, bortezomib, and dexamethasone. After one cycle of therapy, lambda light chains normalized with an improvement in bruising. Diagnostic delays for cardiac patients are concerning as the median survival rate among these patients, when not treated, is approximately 6 months after the onset of symptoms. Since timely treatment can prevent organ damage, clinicians should be aware of specific clinical signs such as raccoon eyes and the importance of systemic evaluation for a prompt diagnosis.

Recent proteome and transcriptome profiling of Alzheimer's disease (AD) brains reveals RNA splicing dysfunction and U1 small nuclear ribonucleoprotein (snRNP) pathology containing U1-70K and its N-terminal 40-KDa fragment (N40K). Here we present a causative role of U1 snRNP dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70K. N40K-Tg recapitulates N40K insolubility, erroneous splicing events, neuronal degeneration and cognitive impairment. Specifically, N40K-Tg shows the reduction of GABAergic synapse components (e.g., the GABA receptor subunit of GABRA2), and concomitant postsynaptic hyperexcitability that is rescued by a GABA receptor agonist. Crossing of N40K-Tg and the 5xFAD amyloidosis model indicates that the RNA splicing defect synergizes with the amyloid cascade to remodel the brain transcriptome and proteome, deregulate synaptic proteins, and accelerate cognitive decline. Thus, our results support the contribution of U1 snRNP-mediated splicing dysfunction to AD pathogenesis.

Systemic light chain (AL) amyloidosis is caused by a B-cell (most commonly plasma cell) clone that produces a toxic light chain that forms amyloid fibrils in tissues and causes severe, progressive organ dysfunction. The clinical presentation is protean, and patients are usually extremely frail, thus requiring careful adaptation of the treatment approach. However, the severity of organ involvement can be accurately assessed with biomarkers that allow a sharp prognostic stratification and precise tailoring of the treatment strategy. Moreover, the availability of biomarker-based response criteria also allows adjustment of the treatment approach over time. The recent completion of 3 large randomized clinical trials has offered new evidence for designing appropriate treatments. All this information has recently been integrated in the joint guidelines of the International Society of Amyloidosis and the European Hematology Association for the treatment of AL amyloidosis. Other clinical trials are underway testing new agents directed against the amyloid clone and the amyloid deposits. Our understanding of the peculiarities of the amyloid clone, as well as our ability to detect residual clonal disease and improve organ dysfunction, are also being refined and will result in more precise personalization of the treatment approach.

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder with multiple clinical presentations. The diagnosis of AL amyloidosis requires a high index of suspicion, making a delay in diagnosis common, which contributes to the high early mortality seen in this disease. Establishing the diagnosis of AL amyloidosis requires the demonstration of tissue deposition of amyloid fibrils. A bone marrow biopsy and fat pad aspirate performed concurrently have a high sensitivity for the diagnosis of AL amyloidosis and negate the need for organ biopsies in most patients. An accurate diagnosis requires amyloid typing via additional testing, including tissue mass spectrometry. Prognostication for AL amyloidosis is largely driven by the organs impacted. Cardiac involvement represents the single most important prognostic marker, and the existing staging systems are driven by cardiac biomarkers. Apart from organ involvement, plasma cell percentage on the bone marrow biopsy, specific fluorescence in situ hybridization findings, age at diagnosis, and performance status are important prognostic markers. This review elaborates on the diagnostic testing and prognostication for patients with newly diagnosed AL amyloidosis.

Technetium-99m (99mTc)-labeled pyrophosphate (PYP) and 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) are currently the most established imaging agents for the diagnosis of cardiac amyloidosis, being able to distinguish light chain (AL) from transthyretin (TTR) type of the disease. We present a pattern of increased uptake in all soft tissues, sparing the organs that are usually most affected.

BACKGROUND Amyloid deposition in the thyroid gland can be primary or secondary and can result in goiter. There have been previous reports of amyloid goiter and thyroid lipomatosis or fatty infiltration. Papillary thyroid carcinoma is the most common thyroid malignancy. We report a rare case of a 54-year-old woman with papillary thyroid carcinoma associated with secondary amyloid goiter and thyroid lipomatosis. CASE REPORT A 54-year-old woman with chronic pyelonephritis and bronchiectasis presented with compressive symptoms due to an enlarged thyroid gland. Thyroid function test results were in the normal range and serum thyroid autoantibodies and serum calcitonin levels were undetectable. Cervical ultrasound showed a diffusely swollen thyroid and a well-defined nodule in the right lobe, of which fine-needle aspiration cytology was suspicious for follicular neoplasm. Computed tomography showed an enlarged thyroid with low attenuation, suggestive of diffuse lipomatosis of the gland. Total thyroidectomy was performed, and a histopathology study indicated the presence of papillary carcinoma and diffuse lipomatosis of the thyroid gland with amyloid deposition. The patient was later diagnosed with secondary amyloidosis. CONCLUSIONS The presentation of secondary amyloidosis as a diffuse goiter with extensive fatty infiltration must be considered in the differential diagnosis of thyroid enlargement, especially those with rapid onset, and particularly in patients with a history of chronic inflammatory disorders or chronic infections predisposing to amyloid deposition. Rarely, differentiated thyroid carcinoma is found within an amyloid goiter and it must be excluded in the differential diagnosis.

Limited data exists on patients with cardiac amyloidosis (CA) in India, due to underdiagnosis and late presentation. We present single centre data from 13 patients over a 4 year period with a median age of 65 years. A majority presented with symptomatic heart failure (69%) and eight patients had confirmed AL amyloidosis. At the end of the follow up period, 46% patients died, with 30% of the overall cohort dead within six months. Among the survivors, 71% continue to have NYHA grade III/IV symptoms. A suggested algorithm for earlier diagnosis in resource constrained settings is also presented.

Gastrointestinal (GI) involvement by chronic lymphocytic leukemia (CLL) is quite uncommon and generally presents with GI bleeding, abdominal pain, and obstruction. However, presentation of CLL as discrete masses without GI symptoms is very rare. A notable complication for patients with CLL is infection due to immunological dysregulation and is typically caused by encapsulated bacteria involving the respiratory tract while viral infections often happen post treatment. Here we present a 78-years-old female with history of treatment-naïve CLL who was incidentally found to have discrete colonic masses secondary to CLL, as well as cytomegalovirus (CMV) and herpes simplex virus (HSV) infections during endoscopic studies for colostomy reversal. On follow-up computed tomography, she was found to have pulmonary amyloidosis as well. We recommend that gastrointestinal tract evaluation should be a part of the complete assessment of the treatment response and remission status in CLL patients to permit early and appropriate therapeutic intervention.

The presence of depressive symptoms prior to hematopoietic stem cell transplantation (HSCT) is a common experience, with long-term impacts on survival. Using the National Institute of Mental Health Research Domain Criteria (RDoC) framework, this study sought to characterize depressive symptoms in patients prior to HSCT through exploratory factor analysis and to determine whether depressive factors were significant predictors of long-term survival. Individuals were included in the study if they were preparing to undergo HSCT and endorsed depressive symptoms measured by the Beck Depression Inventory-II (BDI-II). Patients were scheduled to undergo transplantation between 2005 and 2010. Survival analyses were conducted in 2022 to assess long-term outcomes. The primary outcomes were exploring the factor structure of the BDI-II and conducing univariate and multivariate Cox regression analyses of depression symptoms and known demographic and disease characteristics that impact survival. Of the 695 participants included in the study, most were male, middle aged (mean age, 55.08 ± 11.75 years), white, and married. Exploratory factor analysis revealed a 4-factor structure consisting of "negative valence systems: internalizing" (eg, worthlessness, guilt), "arousal and threat" (eg, agitation, irritability), "arousal and regulatory systems" (eg, loss of energy, fatigue), and "negative valence systems: externalizing" (eg, loss of pleasure, loss of interest). Univariate survival analyses identified age, sex, disease type, acute graft-versus-host disease (GVHD), and negative valence systems: externalizing as significant predictors of survival. Transplant type, chronic GVHD, performance status, and the other 3 depression factor structures were not significant in univariate models. In the multivariate model, older age (hazard ratio [HR], 1.031; 95% confidence interval [CI], 1.021 to 1.041; P < .001) and presence of negative valence systems: externalizing symptoms (HR, 1.132; 95% CI, 1.030 to 1.244; P = .010) were significant predictors of shorter survival. Additionally, individuals diagnosed with acute leukemia were significantly more likely to have shorter survival compared to those with other disease types, including amyloidosis (HR, .362; 95% CI, .229 to .575; P < .001) and non-Hodgkin lymphoma (HR, .526; 95% CI, .349 to .793; P = .002). Exploratory factor analysis of depressive symptoms mapped well onto the RDoC constructs. Loss of pleasure and loss of interest, two key components of depression, were predictive of shorter survival. Exploration of key components of depression rather than the total depression score may provide important prognostic information for long-term survivorship and may help inform future and more individualized care.

The care of systemic amyloidosis has improved dramatically due to improved awareness, accurate diagnostic tools, the development of powerful prognostic and companion biomarkers, and a continuous flow of innovative drugs, which translated into the blooming of phase 2/3 interventional studies for light chain (AL) and transthyretin (ATTR) amyloidosis. The unprecedented availability of effective drugs ignited great interest across various medical specialties, particularly among cardiologists who are now recognizing cardiac amyloidosis at an extraordinary pace. In all amyloidosis referral centers, we are observing a substantial increase in the prevalence of wild-type transthyretin (ATTRwt) cardiomyopathy, which is now becoming the most common form of cardiac amyloidosis. This review focuses on the oral drugs that have been recently introduced for the treatment of ATTR cardiac amyloidosis, for their ease of use in the clinic. They include both old repurposed drugs or fit-for-purpose designed compounds which bind and stabilize the TTR tetramer, thus reducing the formation of new amyloid fibrils, such as tafamidis, diflunisal, and acoramidis, as well as fibril disruptors which have the potential to promote the clearance of amyloid deposits, such as doxycycline. The development of novel therapies is based on the advances in the understanding of the molecular events underlying amyloid cardiomyopathy.

The mammalian 14-3-3 family comprises seven intrinsically unstructured, evolutionarily conserved proteins that bind >200 protein targets, thereby modulating cell-signaling pathways. The presence of 14-3-3 proteins in cerebrospinal fluid provides a sensitive and specific biomarker of neuronal damage associated with Alzheimer's disease (AD), Creutzfeldt-Jakob disease (CJD), spongiform encephalitis, brain cancers, and stroke. We observed significant enrichment of 14-3-3 paralogs G, S, and Z in human brain aggregates diagnostic of AD. We used intra-aggregate crosslinking to identify 14-3-3 interaction partners, all of which were significantly enriched in AD brain aggregates relative to controls. We screened FDA-approved drugs in silico for structures that could target the 14-3-3G/hexokinase interface, an interaction specific to aggregates and AD. C. elegans possesses only two 14-3-3 orthologs, which bind diverse proteins including DAF-16 (a FOXO transcription factor) and SIR-2.1 (a sensor of nutrients and stress), influencing lifespan. Top drug candidates were tested in C. elegans models of neurodegeneration-associated aggregation and in a human neuroblastoma cell-culture model of AD-like amyloidosis. Several drugs opposed aggregation in all models assessed and rescued behavioral deficits in C. elegans AD-like neuropathy models, suggesting that 14-3-3 proteins are instrumental in aggregate accrual and supporting the advancement of drugs targeting 14-3-3 protein complexes with their partners.

Amyloidosis is a group of diverse disorders caused by misfolded proteins that aggregate into insoluble fibrils and ultimately cause organ damage. In medical practice, amyloidosis classification is based on the amyloid precursor protein type, of which amyloid immunoglobulin light chain, amyloid transthyretin, amyloid leukocyte chemotactic factor 2, and amyloid derived from serum amyloid A protein are the most common. Distinct mechanisms appear to be predominantly operational in the pathogenesis of particular types of amyloidosis, including increased protein precursor synthesis, somatic or germ line mutations, and inherent instability in the precursor protein in its wild form. An increased supply of misfolded proteins and/or a decreased capacity of the protein quality control systems can result in an imbalance that leads to increased circulation of misfolded proteins. Although the detection of mature fibrils is the basis for diagnosis of amyloidosis, a growing body of evidence has implicated the prefibrillar species as proteotoxic and key contributors to the development of the disease.