The transcription factor, p53, is critical for many important cellular functions involved in genome integrity, including cell cycle control, DNA damage response, and apoptosis. Disruption of p53 results a wide range disorders cancer, metabolic diseases, neurodegenerative diseases. Alzheimer's disease (AD) disorder characterized by protein aggregates that contribute to pathology. Although known aggregate, its propensity aggregate AD has never been assessed. Moreover, neuropathology includes...

Abstract Tau aggregates propagate in brain cells and transmit to neighboring as well anatomically connected regions by prion-like mechanisms. Soluble tau (tau oligomers) are the most toxic species that initiate neurodegeneration tauopathies, such Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB). Exogenous have been shown be internalized cells; however, precise cellular molecular mechanisms underlie internalization of oligomers (TauO) remain...

Abstract Oligomeric assemblies of tau and the RNA-binding proteins (RBPs) Musashi (MSI) are reported in Alzheimer’s disease (AD). However, role MSI interaction their aggregation process its effects nor clearly known neurodegenerative diseases. Here, we investigated expression cellular localization MSI1 MSI2 brains tissues (AD), amyotrophic lateral sclerosis (ALS) frontotemporal dementia (FTD) as well wild-type mice knock-out P301L mouse models. We observed that formation pathologically...

Ubiquitin-modified tau aggregates are abundantly found in human brains diagnosed with Alzheimer's disease (AD) and other tauopathies. Soluble oligomers (TauO) the most neurotoxic species that propagate pathology elicit cognitive deficits, but whether ubiquitination contributes to formation spreading is not fully understood. Here, we observed K63-linked, K48-linked, ubiquitinated TauO accumulated at higher levels AD compared age-matched controls. Using mass spectrometry analyses, identified...

Pathological tau aggregates cause cognitive decline in neurodegenerative tauopathies, including Alzheimer’s disease (AD). These are prevalent within intracellular compartments. Current immunotherapies have shown limited efficacy clearing and improving cognition clinical trials. In this study, we developed toxic conformation–specific monoclonal antibody-2 (TTCM2), which selectively recognized pathological brain tissues from patients with AD, dementia Lewy bodies (DLB), progressive...

Abstract The pathological aggregation and accumulation of tau, a microtubule-associated protein, is common feature amongst more than 18 different neurodegenerative diseases that are collectively known as tauopathies. Recently, it has been demonstrated the soluble hydrophobic tau oligomers highly toxic in vitro due to their capacity towards seeding misfolding, thereby propagating pathology seen across diseases. Modulating state through use small molecules could be useful therapeutic strategy...

The pathological aggregation of tau plays an important role in Alzheimer's disease and many other related neurodegenerative diseases, collectively referred to as tauopathies. Recent evidence has demonstrated that oligomers, small soluble prefibrillar aggregates, are highly toxic due their strong ability seed misfolding propagate the pathology seen across different diseases. We previously showed novel curcumin derivatives affect preformed oligomer pathways by promoting formation more...

Mild traumatic brain injury accounts for the majority of head injuries and has been correlated with neurodegeneration dementia. While repetitive mild is highly to neurodegeneration, correlation a single still unclear. Because tau aggregates are main form induced pathology, toxic forms protein most likely play role in development post-mild neurodegeneration. Therefore, it becomes crucial characterize properties soluble versus injury. Herein, we isolated oligomers from wild-type mice exposed...

Abstract The exact mechanisms leading to neurodegeneration in Alzheimer's disease (AD) and other tauopathies are not yet entirely understood. However, it is known that several RNA‐binding proteins (RBPs) form toxic aggregates also interact with tau such granules tauopathies, including AD. Musashi (MSI) family of RBPs, consisting two homologues: Musashi1 Musashi2, have been extensively investigated neurodegenerative diseases. Here, using a inducible HEK (iHEK) model we investigate whether MSI...

Abstract The pathological hallmark of synucleinopathies, including Parkinson’s disease (PD), is the aggregation α-synuclein (α-Syn) protein. Even so, tau protein pathology abundantly found in these diseases. Both α-Syn and can exist as polymorphic aggregates, a phenomenon that has been widely studied, mostly their fibrillar assemblies. We have previously discovered addition to oligomers, oligomeric also present brain tissues patients with PD dementia Lewy bodies (DLB). However, effect...

Abstract The microtubule-associated protein tau is implicated in the formation of oligomers and fibrillar aggregates that evade proteostasis control spread from cell-to-cell. Tau pathology accompanied by sustained neuroinflammation and, while release alarmin mediators aggravates disease at late stages, early inflammatory responses encompass protective functions. This case Ca 2+ -binding S100B protein, an astrocytic which augmented AD has been recently as a regulator, acting over amyloid β...

Alzheimer's disease (AD) is marked by cytoplasmic proteinopathies, primarily involving misfolded Tau protein. Pathogenic species, such as soluble oligomers and fibrils, disrupt RNA metabolism, though the mechanisms are unclear. Recent research indicates that has a crucial role in aggregation. Our study builds on this noting significant co-deposition of RNA-Binding Proteins (RBPs) with AD Frontotemporal dementia (FTLD) brains. Using molecular cellular techniques, we investigate interaction...

Alzheimer's disease, a progressive neurodegenerative affects learning and memory resulting from cholinergic dysfunction. Scopolamine has been employed to induce disease-like pathology in vivo vitro through alteration of system. N-benzylcinnamide (PT-3), purified Piper submultinerve, shown exhibit neuroprotective properties against amyloid-β-induced neuronal toxicity rat cortical primary cell culture improve spatial aged rats alleviating oxidative stress. We proposed hypothesis that PT3...

Amyloid aggregates of specific proteins constitute important pathological hallmarks in many neurodegenerative diseases, defining neuronal degeneration and disease onset. Recently, increasing numbers patients show comorbidities overlaps between multiple presenting distinct phenotypes. Such are often accompanied by colocalizations more than one amyloid protein, prompting the question whether direct interactions different could generate heterotypic amyloids. To answer this question, we...

The misfolding and aggregation of the tau protein into neurofibrillary tangles constitutes a central feature tauopathies. Traumatic brain injury (TBI) has emerged as potential risk factor, triggering onset progression Our previous research revealed distinct polymorphisms in soluble oligomers originating from single versus repetitive mild TBIs. However, mechanisms orchestrating dissemination TBI brain-derived polymorphs (TBI-BDTPs) remain elusive. In this study, we explored whether TBI-BDTPs...

Hexanucleotide repeat expansion in C9orf72 is one of the most common causes amyotrophic lateral sclerosis and frontotemporal dementia. The hexanucleotide expansion, formed by GGGGCC (G4C2) repeats, leads to production five dipeptide protein repeats (DPRs) via repeat-associated non-AUG translation. Among Gly-Arg, Pro-Arg, Gly-Ala form neuronal inclusions that contain aggregates peptides. Several studies have attempted model DPR-associated toxicity using various lengths, which suggests a...

The pathological hallmark of many neurodegenerative diseases is the accumulation characteristic proteinaceous aggregates. Parkinson's disease and dementia with Lewy bodies can be characterized as synucleinopathies due to abnormal protein alpha-synuclein (α-Syn). Studies have shown amyloidogenic proteins such α-Syn tau exist polymorphic aggregates, a theory widely studied mostly in their fibrillar morphology. It now well understood that an intermediate state oligomers, are most toxic species....

Tau protein blood levels dependent on its distribution to peripheral organs and possible elimination from the body. Thus, of CSF-derived tau was explored, especially since there is a transition blood-based biomarkers emerging idea that pathology may spread beyond brain. Near infrared fluorescence (NIRF) mainly used analyze (tau-NIRF) after intracisternal or intravenous injection. There striking uptake blood- tau-NIRF by skeletal structures, liver, small intestine (duodenum), gall bladder,...

Amyloid-β peptides and hyper-phosphorylated tau are the main pathological hallmarks of Alzheimer's disease (AD). Given recent failure several large-scale clinical trials lack disease-modifying pharmacological treatments, there is an urgent need to develop alternative therapies. A grade human CTX0E03 neural stem cell line has recently passed phase I in people with stroke. However, this not been investigated other neurodegenerative disorders. This study investigates survival cells under...

Abstract Background Tauopathies, including Alzheimer’s Disease and Frontotemporal Dementia, are characterized as intracellular lesions composed of aggregated tau proteins. Soluble oligomers shown to be one the most toxic species responsible for spread pathology. Recent studies have found that several proteins such amyloid b, a‐synuclein, TDP‐43 can aggregate tau. In this study, we investigated ability small metabolites like C9orf72 associated dipeptide protein repeats (DPRs) interact with...

Abstract Background The misfolding and aggregation of the tau protein into neurofibrillary tangles constitute a central feature tauopathies. Traumatic brain injury (TBI) has emerged as potential risk factor, triggering onset progression Our previous research revealed distinct polymorphisms in soluble oligomers originating from single versus repetitive mild TBIs. However, mechanisms orchestrating dissemination TBI brain‐derived polymorphs (TBI‐BDTPs) remain elusive. Method We explored whether...