Search Results (77)

The design and synthesis of a small library of 2-styrylquinoline derivatives containing a push-pull system, aimed at displacing their fluorescence emission towards the NIR region, is described. We describe here their synthesis, fluorescent characterization and pharmacological evaluation against different amyloid proteins. Their study showed that these compounds are capable to change their spectroscopic properties upon protein interaction, resulting in changes in the absorption and emission wavelengths, together with increased fluorescence intensity. They also showed sensitivity to pH and environment polarity, exhibiting red shifts in lower polarity environments with regard to aqueous media. Inner charge transfer is observed and employed for detecting the interaction of these compounds with protein aggregates. The study of the alterations in the fluorescence intensity allows to calculate the dissociation constant values for the protein-sensor interaction. These spectroscopic results were the basis for the use of these compounds to visualize β-amyloid plates with selectivity over phosphorylated tau in samples of cerebral tissue from deceased Alzheimer patients under fluorescence microscopy, using immunofluorescence techniques. Pharmacological assays showed that the compounds inhibit the aggregation of the Aβ_1–42 and AcPHF6 peptides, representing tau protein. They also showed neuroprotective activity following okadaic acid insult. Full article

Dementia with Lewy bodies (DLB), the second common primary degenerative neurocognitive disorder after Alzheimer disease (AD), frequently presents concurrent co-pathologies that impact clinical presentation and progression. Neuropathological studies have demonstrated a high prevalence of coexistent AD-related neuropathological changes (ADNC), TAR DNA-binding protein 43 (TDP-43) proteinopathies, and cardiac and aging-related disorders, while frontotemporal lobar degeneration (FTLD) and tau-related syndromes play a minor role as DLB-related co-pathologies. Cerebrovascular lesions, including cerebral amyloid angiopathy, are the most prevalent non-neurodegenerative co-pathologies. Cardiovascular disorders, hypertension, and hyperlipidemia are also frequent comorbidities. Due to their high prevalence and clinical impact on DLB patients, clinical trials should account for these and other co-pathologies in their design and selection. Evaluation of these co-pathologies using and interpreting biomarkers may allow greater clinical diagnostic accuracy and the opportunity to better predict clinical progression. Therefore, there is an increasing need for biomarkers in dementia research. This review discusses the kind and frequency of the different co-pathologies in DLB and their clinical impact. It evaluates the possible value of disease-specific biomarkers and how they are helpful in the assessment and prevention of DLB and its co-pathologies. Full article

Background/Objectives: Neurodegenerative proteinopathies, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB), are increasingly prevalent worldwide mainly due to population aging. These conditions are marked by complex etiologies, overlapping pathologies, and progressive clinical decline, with significant consequences for patients, caregivers, and healthcare systems. This review aims to synthesize evidence on the healthcare complexities of major neurodegenerative proteinopathies to highlight current knowledge gaps, and to inform future care models, policies, and research directions. Methods: We conducted a comprehensive literature search in PubMed/MEDLINE using combinations of MeSH terms and keywords related to neurodegenerative diseases, proteinopathies, diagnosis, sex, management, treatment, caregiver burden, and healthcare delivery. Studies were included if they addressed the clinical, pathophysiological, economic, or care-related complexities of aging-related neurodegenerative proteinopathies. Results: Key themes identified include the following: (1) multifactorial and unclear etiologies with frequent co-pathologies; (2) long prodromal phases with emerging biomarkers; (3) lack of effective disease-modifying therapies; (4) progressive nature requiring ongoing and individualized care; (5) high caregiver burden; (6) escalating healthcare and societal costs; and (7) the critical role of multidisciplinary and multi-domain care models involving specialists, primary care, and allied health professionals. Conclusions: The complexity and cost of neurodegenerative proteinopathies highlight the urgent need for prevention-focused strategies, innovative care models, early interventions, and integrated policies that support patients and caregivers. Prevention through the early identification of risk factors and prodromal signs is critical. Investing in research to develop effective disease-modifying therapies and improve early detection will be essential to reducing the long-term burden of these disorders. Full article

Transactive response DNA-binding protein of 43 kDa (TDP-43) and tau proteins play critical roles in neurodegenerative diseases, particularly frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). The co-occurrence of TDP-43 and tau pathologies raises questions about their role in disease progression. This review explores the simultaneous presence of tau and TDP-43 co-pathologies, emphasizing their molecular interactions and the resultant neuropathological implications. Additionally, we provide representative examples of their clinical presentations, neuroimaging, and neuropathological findings associated with FTLD-TDP and FTLD-tau, emphasizing the need for a comprehensive understanding of these intertwined pathologies. We analyze various clinical scenarios, including argyrophilic grain disease (AGD), primary age-related tauopathy (PART), and limbic predominant age-related TDP-43 encephalopathy (LATE), to elucidate the complex relationship between these proteinopathies. From the literature, the co-occurrence of tau and TDP-43 is linked to more severe and poorer clinical outcomes compared to isolated pathologies. This review underscores the necessity of considering co-pathologies in the context of FTLD, as they may act as accelerators of cognitive decline. This highlights the importance of integrated approaches in diagnosing and treating neurodegenerative conditions characterized by tau and TDP-43 misfolding. Understanding the interplay between these molecular markers is vital for advancing therapeutic strategies for such disorders. Full article

Neurodegenerative diseases (NDDs) that are characterized by the accumulation of alpha-synuclein (α-syn) aggregates in both neurons and the non-neuronal cells of the brain are called synucleinopathies. The most common synucleinopathies includes Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Significant progress has been made in the development of positron emission tomography (PET) radiotracers for synucleinopathies, yielding several α-syn tracers that have entered clinical studies. However, selective α-syn imaging still faces inherent challenges. This review provides a comprehensive overview of the progress in α-syn PET radiotracers from three angles: Alzheimer’s disease (AD)-derived scaffolds, representative compound scaffolds and analogs, and the identification of α-syn tracers through high-throughput screening (HTS). We discuss the characteristics, advantages, and limitations of the tracers for preclinical and clinical application. Finally, future directions in the development of radioligands for proteinopathies are discussed. There is no clinical available PET radiotracer for imaging α-syn aggregates, but these advances have laid a key foundation for non-invasive α-syn imaging and early diagnosis of synucleinopathies. Full article

Familial Alzheimer’s disease (FAD) is a complex multifactorial disorder clinically characterized by cognitive impairment and memory loss. Pathologically, FAD is characterized by intracellular accumulation of the protein fragment Aβ42 (iAβ), hyperphosphorylated microtubule-associated protein TAU (p-TAU), and extensive degeneration of basal forebrain cholinergic neurons of the nucleus basalis of Meynert (NbM) and the medial septal nucleus (MSN), mainly caused by mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and PSEN2 gene. Since the dopaminergic system may contribute to FAD symptoms, alterations in the nigro-hippocampal pathway may be associated with cognitive impairment in FAD. Interestingly, p-α-synuclein (p-α-Syn), Aβ, and p-TAU have been found to coexist in vulnerable regions of postmortem AD brains. However, the mechanism by which Aβ, p-TAU, and α-Syn coexist in DAergic neurons in AD brains has not been determined. We generated PSEN1 I416T dopaminergic-like neurons (DALNs) from I416T menstrual stromal cells (MenSCs) in NeuroForsk 2.0 medium for 7 days and then cultured them in minimal culture medium (MCm) for another 4 days. On day 11, DALNs were analyzed for molecular and pathological markers by flow cytometry and fluorescence microscopy. We found that mutant DALNs showed increased accumulation of iAβ as well as increased phosphorylation of TAU at S202/T205 compared to WT DALNs. Thus, mutant DALNs exhibited typical pathological hallmarks of Alzheimer’s disease. Furthermore, PSEN1 I416T DALNs showed concomitant signs of OS as evidenced by the appearance of oxidized sensor protein DJ-1 (i.e., DJ-1C106-SO₃) and apoptotic markers TP53, pS63-c-JUN, PUMA, and cleavage caspase 3 (CC3). Notably, these DALNs exhibited PD-associated proteins such as intracellular accumulation of α-Syn (detected as aggregates of pS129-α-Syn) and phosphorylation of LRRK2 kinase at residue S935. In addition, mutant DALNs showed a 17.16- and 6.17-fold decrease in DA-induced Ca²⁺ flux, compared to WT DALNs. These observations suggest that iAβ and p-TAU, together with p-α-Syn, and p-LRRK2 kinase, may damage DAergic neurons and thereby contribute to the exacerbation of neuropathologic processes in FAD. Remarkably, the LRRK2 inhibitor PF-06447475 (PF-475) significantly reversed PSEN1 I416T-induced neuropathological markers in DAergic neurons. PF-465 inhibitor reduced iAβ, oxDJ-1C106-SO₃, and p-TAU. In addition, this inhibitor reduced pS935-LRRK2, pS129-αSYN, pS63-c-JUN, and CC3. We conclude that the observed neuroprotective effects of PF-475 are due to direct inhibition of LRRK2 activity and that the LRRK2 protein is upstream of the molecular cascade of apoptosis and proteinopathy. Our results suggest that PF-475 is an effective neuroprotective agent against endogenous PSEN1 I416T-induced neurotoxicity in DALNs coexisting with Parkinson’s disease markers. Therefore, PF-475 may be of great therapeutic value in FAD. Full article

TAR DNA-binding protein 43 kDa (TDP-43) proteinopathies are a group of neurodegenerative diseases (NDs) characterized by the abnormal accumulation of the TDP-43 protein in neurons and glial cells. These proteinopathies are associated with several NDs, including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and some forms of Alzheimer’s disease. Yeast models have proven valuable in ND research due to their simplicity, genetic tractability, and the conservation of many cellular processes shared with higher eukaryotes. For several decades, Saccharomyces cerevisiae has been used as a model organism to study the behavior and toxicity of TDP-43, facilitating the identification of genes and pathways that either exacerbate or mitigate its toxic effects. This review will discuss evidence showing that yeast models of TDP-43 exhibit defects in proteostasis, mitochondrial function, autophagy, and RNA metabolism, which are key features of TDP-43-related NDs. Additionally, we will explore how modulating proteins involved in these processes reduce TDP-43 toxicity, aiding in restoring normal TDP-43 function or preventing its pathological aggregation. These findings highlight potential therapeutic targets for the treatment of TDP-43-related diseases. Full article

Depositions of protein aggregates are typical pathological hallmarks of various neurodegenerative diseases (NDs). For example, amyloid-beta (Aβ) and tau aggregates are present in the brain and plasma of patients with Alzheimer’s disease (AD); α-synuclein in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); mutant huntingtin protein (Htt) in Huntington’s disease (HD); and DNA-binding protein 43 kD (TDP-43) in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). The same misfolded proteins can be present in multiple diseases in the form of mixed proteinopathies. Since there is no cure for all these diseases, understanding the mechanisms of protein aggregation becomes imperative in modern medicine, especially for developing diagnostics and therapeutics. A Multimer Detection System (MDS) was designed to distinguish and quantify the multimeric/oligomeric forms from the monomeric form of aggregated proteins. As the unique epitope of the monomer is already occupied by capturing or detecting antibodies, the aggregated proteins with multiple epitopes would be accessible to both capturing and detecting antibodies simultaneously, and signals will be generated from the oligomers rather than the monomers. Hence, MDS could present a simple solution for measuring various conformations of aggregated proteins with high sensitivity and specificity, which may help to explore diagnostic and treatment strategies for developing anti-aggregation therapeutics. Full article

Preeclampsia (preE) is a severe multisystem hypertensive syndrome of pregnancy associated with ischemia/hypoxia, angiogenic imbalance, apolipoprotein E (ApoE)-mediated dyslipidemia, placental insufficiency, and inflammation at the maternal–fetal interface. Our recent data further suggest that preE is associated with impaired autophagy, vascular dysfunction, and proteinopathy/tauopathy disorder, similar to neurodegenerative diseases such as Alzheimer’s disease (AD), including the presence of the cis stereo-isoform of phosphorylated tau (cis P-tau), amyloid-β, and transthyretin in the placenta and circulation. This review provides an overview of the factors that may lead to the induction and accumulation of cis P-tau-like proteins by focusing on the inactivation of peptidyl-prolyl cis–trans isomerase (Pin1) that catalyzes the cis to trans isomerization of P-tau. We also highlighted the novel role of the Pin1-cis P-tau-ApoE axis in the development of preE, and propagation of cis P-tau-mediated abnormal protein aggregation (tauopathy) from the placenta to cerebral tissues later in life, leading to neurodegenerative conditions. In the case of preE, proteinopathy/tauopathy may interrupt trophoblast differentiation and induce cell death, similar to the events occurring in neurons. These events may eventually damage the endothelium and cause systemic features of disorders such as preE. Despite impressive research and therapeutic advances in both fields of preE and neurodegenerative diseases, further investigation of Pin1-cis P-tau and ApoE-related mechanistic underpinnings may unravel novel therapeutic options, and new transcriptional and proteomic markers. This review will also cover genetic polymorphisms in the ApoE alleles leading to dyslipidemia induction that may regulate the pathways causing preE or dementia-like features in the reproductive age or later in life, respectively. Full article

Protein aggregation may lead to detrimental changes in brain and several other tissues. Amyloids or large protein aggregates are formed in different brain areas under multiple diseases classified as proteinopathies. However, our understanding of the initiation, elongation, and spread of amyloid aggregates is limited. Our current knowledge about these diseases is generic and we lack specific mechanisms for several diseases affecting memory, movement, and behavior. Multiple studies have indicated the involvement of vesicular transport in the spread of aggregates formed inside the brain. For example, the trafficking of amyloid precursor protein (APP) occurs from Golgi to Endosome using an adapter protein complex. Amyloids, once formed, may also affect cholesterol (an important membrane constituent), homeostasis, and overall membranous transport. A disruption of vesicular transport could be deleterious for synaptic neurotransmission. Alterations caused by amyloid proteins in vesicular transport may form a feedback loop and thus contribute further to the pathogenesis of Alzheimer’s disease (AD) and many others. In this review, we are providing recent updates on this crisscross puzzle and exploring an evolving correlation between amyloid formation and vesicular transport. Full article

Alzheimer’s disease (AD) is the most common type of dementia worldwide. The etiopathogenesis of this disease remains unknown. Currently, several hypotheses attempt to explain its cause, with the most well-studied being the cholinergic, beta-amyloid (Aβ), and Tau hypotheses. Lately, there has been increasing interest in the role of immunological factors and other proteins such as alpha-synuclein (α-syn) and transactive response DNA-binding protein of 43 kDa (TDP-43). Recent studies emphasize the role of tunneling nanotubes (TNTs) in the spread of pathological proteins within the brains of AD patients. TNTs are small membrane protrusions composed of F-actin that connect non-adjacent cells. Conditions such as pathogen infections, oxidative stress, inflammation, and misfolded protein accumulation lead to the formation of TNTs. These structures have been shown to transport pathological proteins such as Aβ, Tau, α-syn, and TDP-43 between central nervous system (CNS) cells, as confirmed by in vitro studies. Besides their role in spreading pathology, TNTs may also have protective functions. Neurons burdened with α-syn can transfer protein aggregates to glial cells and receive healthy mitochondria, thereby reducing cellular stress associated with α-syn accumulation. Current AD treatments focus on alleviating symptoms, and clinical trials with Aβ-lowering drugs have proven ineffective. Therefore, intensifying research on TNTs could bring scientists closer to a better understanding of AD and the development of effective therapies. Full article

Aging is the most prominent risk factor for neurodegeneration occurrence. The most common neurodegenerative diseases (NDs), Alzheimer’s (AD) and Parkinson’s (PD) diseases, are characterized by the incidence of proteinopathy, abnormal activation of glial cells, oxidative stress, neuroinflammation, impaired autophagy and cellular senescence excessive for the patient’s age. Moreover, mitochondrial disfunction, epigenetic alterations and neurogenesis inhibition, together with increased blood–brain barrier permeability and gut dysbiosis, have been linked to ND pathogenesis. Since NDs still lack curative treatment, recent research has sought therapeutic options in restoring gut microbiota and supplementing probiotic bacteria-derived metabolites with beneficial action to the host—so called postbiotics. The current review focuses on literature explaining cellular mechanisms involved in ND pathogenesis and research addressing the impact that postbiotics as a whole mixture and particular metabolites, such as short-chain fatty acids (SCFAs), lactate, polyamines, polyphenols, tryptophan metabolites, exopolysaccharides and bacterial extracellular vesicles, have on the ageing-associated processes underlying ND occurrence. The review also discusses the issue of implementing postbiotics into ND prophylaxis and therapy, depicting them as compounds addressing senescence-triggered dysfunctions that are worth translating from bench to pharmaceutical market in response to “silver consumers” demands. Full article

The purpose of this study was to investigate whether plasma biomarkers can help to diagnose, differentiate from Alzheimer disease (AD), and stage cognitive performance in patients with positron emission tomography (PET)-confirmed primary age-related tauopathy, termed tau-first cognitive proteinopathy (TCP) in this study. In this multi-center study, we enrolled 285 subjects with young-onset AD (YOAD; n = 55), late-onset AD (LOAD; n = 96), TCP (n = 44), and cognitively unimpaired controls (CTL; n = 90) and analyzed plasma Aβ42/Aβ40, pTau181, neurofilament light (NFL), and total-tau using single-molecule assays. Amyloid and tau centiloids reflected pathological burden, and hippocampal volume reflected structural integrity. Receiver operating characteristic curves and areas under the curves (AUCs) were used to determine the diagnostic accuracy of plasma biomarkers compared to hippocampal volume and amyloid and tau centiloids. The Mini-Mental State Examination score (MMSE) served as the major cognitive outcome. Logistic stepwise regression was used to assess the overall diagnostic accuracy, combining fluid and structural biomarkers and a stepwise linear regression model for the significant variables for MMSE. For TCP, tau centiloid reached the highest AUC for diagnosis (0.79), while pTau181 could differentiate TCP from YOAD (accuracy 0.775) and LOAD (accuracy 0.806). NFL reflected the clinical dementia rating in TCP, while pTau181 (rho = 0.3487, p = 0.03) and Aβ42/Aβ40 (rho = −0.36, p = 0.02) were significantly correlated with tau centiloid. Hippocampal volume (unstandardized β = 4.99, p = 0.01) outperformed all of the fluid biomarkers in predicting MMSE scores in the TCP group. Our results support the superiority of tau PET to diagnose TCP, pTau181 to differentiate TCP from YOAD or LOAD, and NFL for functional staging. Full article

Alzheimer’s disease (AD) is a neurodegenerative olfactory disorder affecting millions of people worldwide. Alterations in the hexosamine- or glucose-related pathways have been described through AD progression. Specifically, an alteration in glucosamine 6 phosphate isomerase 2 (GNPDA2) protein levels has been observed in olfactory areas of AD subjects. However, the biological role of GNPDA2 in neurodegeneration remains unknown. Using mass spectrometry, multiple GNPDA2 interactors were identified in human nasal epithelial cells (NECs) mainly involved in intraciliary transport. Moreover, GNPDA2 overexpression induced an increment in NEC proliferation rates, accompanied by transcriptomic alterations in Type II interferon signaling or cellular stress responses. In contrast, the presence of beta-amyloid or mutated Tau-P301L in GNPDA2-overexpressing NECs induced a slowdown in the proliferative capacity in parallel with a disruption in protein processing. The proteomic characterization of Tau-P301L transgenic zebrafish embryos demonstrated that GNPDA2 overexpression interfered with collagen biosynthesis and RNA/protein processing, without inducing additional changes in axonal outgrowth defects or neuronal cell death. In humans, a significant increase in serum GNPDA2 levels was observed across multiple neurological proteinopathies (AD, Lewy body dementia, progressive supranuclear palsy, mixed dementia and amyotrophic lateral sclerosis) (n = 215). These data shed new light on GNPDA2-dependent mechanisms associated with the neurodegenerative process beyond the hexosamine route. Full article

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide. Emerging research has challenged the conventional notion of a direct correlation between amyloid deposition and neurodegeneration in AD. Recent studies have suggested that amyloid and Tau deposition act as a central nervous system (CNS) innate immune driver event, inducing chronic microglial activation that increases the susceptibility of the AD brain to the neurotoxicity of infectious insults. Although modifiable risk factors account for up to 50% of AD risk, the mechanisms by which they interact with the core process of misfolded protein deposition and neuroinflammation in AD are unclear and require further investigation. This update introduces a novel perspective, suggesting that modifiable risk factors act as external insults that, akin to infectious agents, cause neurodegeneration by inducing recurrent acute neurotoxic microglial activation. This pathological damage occurs in AD pathology-primed regions, creating a “hit and run” mechanism that leaves no discernible pathological trace of the external insult. This model, highlighting microglia as a pivotal player in risk factor-mediated neurodegeneration, offers a new point of view on the complex associations of modifiable risk factors and proteinopathy in AD pathogenesis, which may act in parallel to the thoroughly studied amyloid-driven Tau pathology, and strengthens the therapeutic rationale of combining immune modulation with tight control of risk factor-driven insults. Full article