Axodendritic targeting of TAU and MAP2 and microtubule polarization in iPSC-derived versus SH-SY5Y-derived human neurons DOI Creative Commons

H. D. Breuer,

Michael J. Bell, Hans Zempel

и другие.

Open Life Sciences, Год журнала: 2024, Номер 19(1)

Опубликована: Янв. 1, 2024

Abstract Cell polarity is crucial in neurons, characterized by distinct axonal and dendritic structures. Neurons generally have one long axon multiple shorter dendrites, marked specific microtubule (MT)-associated proteins, e.g., MAP2 for dendrites TAU axons, while the scaffolding proteins AnkG TRIM46 mark axon-initial-segment. In tauopathies, such as Alzheimer’s disease (AD), sorting, neuronal are disrupted, leading to MT loss. However, modeling studying MTs human cells relevant study of AD TAU-related neurodegenerative diseases (NDD) challenging. To dynamics we compared two cell culture systems: SH-SY5Y-derived neurons (SHN) induced pluripotent stem cell-derived (iN). Using immunostaining EB3-tdTomato time-lapse imaging, found absent SHN but present iN, was both. showed enrichment, respectively, similar mouse primary neurons. Both neuron types exhibited polarized structures, with unidirectional axons bidirectional dendrites. Polymerization speeds were similar; however, iNs had more retrograde growth events, a higher overall number events. Thus, iN both suitable polarity, being particularly if focus not AIS.

Язык: Английский

The potential link between the development of Alzheimer’s disease and osteoporosis DOI Creative Commons

Fariha Nasme,

Jyotirmaya Behera,

Prisha Tyagi

и другие.

Biogerontology, Год журнала: 2025, Номер 26(1)

Опубликована: Янв. 20, 2025

Язык: Английский

Процитировано

0
Pathomechanisms of neuropsychiatric disturbances in atypical parkinsonian disorders: a current view DOI
K. A. Jellinger

Journal of Neural Transmission, Год журнала: 2025, Номер unknown

Опубликована: Фев. 15, 2025

Язык: Английский

Процитировано

0
The tau isoform 1N4R confers vulnerability of MAPT knockout human iPSC‐derived neurons to amyloid beta and phosphorylated tau‐induced neuronal dysfunction DOI Creative Commons
Sarah Buchholz, Mohamed Aghyad Al Kabbani, Michael J. Bell

и другие.

Alzheimer s & Dementia, Год журнала: 2025, Номер unknown

Опубликована: Фев. 28, 2025

Abstract INTRODUCTION Human tau protein, composed of six brain‐specific isoforms, is a major driver Alzheimer's disease (AD). The role its isoforms however remains unclear and human AD models are scarce. METHODS We generated MAPT – (tau–) knockout (KO) induced pluripotent stem cells (iPSC) using CRISPR/Cas9, differentiated these into glutamatergic neurons, assessed isoform‐specific functions in neurons. used omic‐ approaches, live‐cell imaging, subcompartmental analysis, lentivirus‐based reintroduction specific to investigate isoform‐mediated neuronal dysfunction an model. RESULTS Tau KO iPSC‐derived neurons showed decreased neurite outgrowth axon initial segment length and, notably, resisted amyloid beta oligomer (AβO)–induced activity reduction. Introducing the 1N4R‐tau isoform, but not other confers AβO vulnerability increases KxGS phosphorylation tau, without altering or microtubule modifications. DISCUSSION While impacts development activity, tau‐KO also resistance against insult. likely mediates AβO‐induced phosphorylated toxicity, representing novel prime therapeutic target for AD. Highlights alters growth formation show differential axonal localization depletion protects (AβO)–mediated neurotoxicity. 1N4R toxicity

Язык: Английский

Процитировано

0
Pathological tau activates inflammatory nuclear factor-kappa B (NF-κB) and pT181-Qβ vaccine attenuates NF-κB in PS19 tauopathy mice DOI Open Access
Karthikeyan Tangavelou, Shanya Jiang,

Somayeh Dadras

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 13, 2025

Tau regulates neuronal integrity. In tauopathy, phosphorylated tau detaches from microtubules and aggregates, is released into the extracellular space. Microglia are first responders to tau, a danger/damage-associated molecular pattern (DAMP), which can be cleared by proteostasis activate innate immune response gene expression nuclear factor-kappa B (NF-κB). However, longitudinal NF-κB activation in tauopathies whether pathological (pTau) contributes activity unknown. Here, we oligomers human Alzheimer's disease brain (AD-TO) mouse microglia macrophages reducing IκBα via promoting its secretion peaks at 9- 11-months age PS19Luc + hTauLuc mice, respectively. Reducing pTau pharmacological (DOX), genetic ( Mapt -/- ) or antibody-mediated neutralization (immunization with pT181-Qβ vaccine) reduces activity, together suggest driver of chronic neuroinflammation tauopathies. Neuronal activates microglial constitutively secreting inhibitor IκBα. mice age, Neutralizing vaccine (targeting threonine 181 tau) alleviates tauopathy mice.

Язык: Английский

Процитировано

0
Advancements in Proteolysis Targeting Chimeras for Targeted Therapeutic Strategies in Alzheimer’s Disease DOI Creative Commons

Qiuzhi Zhou,

Weixia Wang, Chunchu Deng

и другие.

Molecular Neurobiology, Год журнала: 2025, Номер unknown

Опубликована: Март 25, 2025

Язык: Английский

Процитировано

0
Alzheimer mimicry: LATE and PART DOI Creative Commons
Nenad Bogdanović,

Una Smailović,

Vesna Jelić

и другие.

Journal of Neural Transmission, Год журнала: 2025, Номер unknown

Опубликована: Март 31, 2025

Язык: Английский

Процитировано

0
Metal Toxicity and Dementia Including Frontotemporal Dementia: Current State of Knowledge DOI Creative Commons
Francesca Gorini, Alessandro Tonacci

Antioxidants, Год журнала: 2024, Номер 13(8), С. 938 - 938

Опубликована: Авг. 1, 2024

Frontotemporal dementia (FTD) includes a number of neurodegenerative diseases, often with early onset (before 65 years old), characterized by progressive, irreversible deficits in behavioral, linguistic, and executive functions, which are difficult to diagnose due their similar phenotypic characteristics other dementias psychiatric disorders. The genetic contribution is utmost importance, although environmental risk factors also play role its pathophysiology. In fact, some metals known produce free radicals, which, accumulating the brain over time, can induce oxidative stress, inflammation, protein misfolding, all these being key features FTD conditions. Therefore, present review aims summarize current evidence about FTD-mainly dealing toxic metal exposure-since identification such potential lead diagnosis promotion policies interventions. This would allow us, reducing exposure pollutants, potentially affect society at large positive manner, decreasing burden conditions on affected individuals overall. Future perspectives, including application Artificial Intelligence principles field, related found so far, introduced.

Язык: Английский

Процитировано

3
Clinicopathological Heterogeneity of Lewy Body Diseases: The Profound Influence of Comorbid Alzheimer Disease DOI Creative Commons

Thomas G Beach,

Geidy E. Serrano, Nan Zhang

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 4, 2024

In recent years, proposals have been advanced to redefine or reclassify Lewy body disorders by merging the long-established entities of Parkinson's disease (PD), dementia (PDD) and with bodies (DLB). These reject International DLB Consortium classification system that has evolved over three decades consensus collaborations between neurologists, neuropsychologists neuropathologists. While Consortium's "one year rule" for separating PD criticized as arbitrary, it a pragmatic effective tool splitting continuum two entities. addition literature supporting non-homogeneity DLB, become increasingly apparent may fundamentally differ in their etiology. Most subjects, well most clinically-presenting might best be classified having "primary synucleinopathy" while clinically-unidentified who also concurrent neuropathology-criteria AD (AD/DLB), those neuropathological amygdala-predominant LBD insufficient diagnosis, "secondary synucleinopathy. Importantly, recognized importance comorbid pathology defining "Low", "Intermediate" "High" subdivisions based on relative brain stages both pathology. If one-year rule from then dividing into subtypes presence severity pathology, is effective, divided groups should statistically important ways. this study we used comprehensive clinicopathological database Arizona Study Aging Neurodegenerative Disorders (AZSAND) empirically test hypothesis. Furthermore, multivariable statistical models hypothesis neuropathology major predictor postmortem The results confirm heterogeneity profound influence

Язык: Английский

Процитировано

2
Pathological study of progressive supranuclear palsy the cases with mutations in Bassoon DOI

Masahiro Wakita,

Hiroaki Yaguchi,

Mika Otuski

и другие.

Neuropathology, Год журнала: 2024, Номер unknown

Опубликована: Окт. 31, 2024

Clinical diagnosis of progressive supranuclear palsy (PSP) is difficult due to various phenotypes. Neuropathologically, PSP defined by neuronal loss in the basal ganglia and brainstem with widespread occurrence neurofibrillary tangles (NFTs) accumulation phosphorylated tau protein neurons glial cells brain. We previously identified point mutation p.Pro3866Ala Bassoon ( BSN ) gene a Japanese family PSP‐like syndrome. newly detected mutations two autopsied cases carrying p.Thr2542Met p.Glu2759Gly, respectively. The case showed neurological symptoms including behavioral abnormalities, cognitive dysfunction, parkinsonism. Brain magnetic resonance imaging (MRI) atrophy midbrain tegmentum hippocampus. Pathologically, moderate severe gliosis was also found substantia nigra, there an almost complete transitional zone cornu ammonis (CA) 1 region subiculum. NFTs were observed globus pallidus, subthalamic nucleus, CA1. 4R tau‐dominant tauopathy detected. p.Glu2759Gly symptoms, right‐dominant motor impairment, right limping gait, postural instability, dysfunction. MRI mild left‐dominant parietal lobe atrophy. thalamus, putamen, tegmentum. Most immunopositive for four‐repeat tau, whereas only few them harbored three‐repeat tau‐positive results pathological study mutations; these new cases. clinical phenotypes similar first symptoms. Accumulation dominant. Further autopsies further elucidation molecular biological mechanism are desirable.

Язык: Английский

Процитировано

2
The Mechanistic Link Between Tau-Driven Proteotoxic Stress and Cellular Senescence in Alzheimer’s Disease DOI Open Access
Karthikeyan Tangavelou, Kiran Bhaskar

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(22), С. 12335 - 12335

Опубликована: Ноя. 17, 2024

In Alzheimer's disease (AD), tau dissociates from microtubules (MTs) due to hyperphosphorylation and misfolding. It is degraded by various mechanisms, including the 20S proteasome, chaperone-mediated autophagy (CMA), 26S macroautophagy, aggrephagy. Neurofibrillary tangles (NFTs) form upon impairment of aggrephagy, eventually, ubiquitin chaperone valosin-containing protein (VCP) heat shock 70 kDa (HSP70) are recruited sites NFTs for extraction ubiquitin-proteasome system (UPS)-mediated degradation. However, degradation in neurons allows be secreted into extracellular space. Secreted can monomers, oligomers, paired helical filaments (PHFs), which seeding competent pathological that endocytosed/phagocytosed healthy neurons, microglia, astrocytes, oligodendrocyte progenitor cells (OPCs), oligodendrocytes, often causing proteotoxic stress eventually triggers senescence. Senescent secrete senescence-associated secretory phenotype (SASP) factors, trigger cellular atrophy, decreased brain volume human AD. molecular mechanisms senescence not entirely understood an emerging area research. Therefore, this comprehensive review summarizes pertinent studies provided evidence sequential degradation, failure, mechanistic link between tau-driven

Язык: Английский

Процитировано

1