Targeting protein kinases for the treatment of Alzheimer's disease: Recent progress and future perspectives

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 261, С. 115817 - 115817

Опубликована: Сен. 14, 2023

Язык: Английский

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Amyloid-β and Phosphorylated Tau are the Key Biomarkers and Predictors of Alzheimer’s Disease

Aging and Disease, Год журнала: 2024, Номер unknown, С. 0 - 0

Опубликована: Янв. 1, 2024

Alzheimer's disease (AD) is a age-related neurodegenerative and major public health concern both in Texas, US Worldwide. This mainly characterized by amyloid-beta (Aβ) phosphorylated Tau (p-Tau) accumulation the brains of patients with AD increasing evidence suggests that these are key biomarkers AD. Both Aβ p-tau can be detected through various imaging techniques (such as positron emission tomography, PET) cerebrospinal fluid (CSF) analysis. The presence individuals, who asymptomatic or have mild cognitive impairment indicate an increased risk developing future. Furthermore, combination often used for more accurate diagnosis prediction progression. Along being disease, it associated other chronic conditions such cardiovascular obesity, depression, diabetes because studies shown comorbid make people vulnerable to In first part this review, we discuss biofluid-based Aβ, p-Tau & plasma could alternative sensitive technique diagnose second part, underlying molecular mechanisms linked how they affect clinical care.

Язык: Английский

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The Enigma of Tau Protein Aggregation: Mechanistic Insights and Future Challenges

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(9), С. 4969 - 4969

Опубликована: Май 2, 2024

Tau protein misfolding and aggregation are pathological hallmarks of Alzheimer's disease over twenty neurodegenerative disorders. However, the molecular mechanisms tau in vivo remain incompletely understood. There two types aggregates brain: soluble (oligomers protofibrils) insoluble filaments (fibrils). Compared to filamentous aggregates, more toxic exhibit prion-like transmission, providing seeds for templated misfolding. Curiously, its native state, is a highly soluble, heat-stable that does not form fibrils by itself, even when hyperphosphorylated. In vitro studies have found negatively charged molecules such as heparin, RNA, or arachidonic acid generally required induce aggregation. Two recent breakthroughs provided new insights into mechanisms. First, an intrinsically disordered protein, undergo liquid-liquid phase separation (LLPS) both inside cells. Second, cryo-electron microscopy has revealed diverse fibrillar conformations associated with different Nonetheless, only core structurally resolved, remainder appears "fuzzy coat". From this review, it further (1) clarify role LLPS aggregation; (2) unveil structural features aggregates; (3) understand involvement fuzzy coat regions oligomer fibril formation.

Язык: Английский

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Structures of AT8 and PHF1 phosphomimetic tau: Insights into the posttranslational modification code of tau aggregation

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(10)

Опубликована: Фев. 26, 2024

The microtubule-associated protein tau aggregates into amyloid fibrils in Alzheimer's disease and other neurodegenerative diseases. In these tauopathies, is hyperphosphorylated, suggesting that this posttranslational modification (PTM) may induce aggregation. Tau also phosphorylated normal developing brains. To investigate how phosphorylation induces fibrils, here we report the atomic structures of two phosphomimetic full-length assembled without anionic cofactors. We mutated key Ser Thr residues to Glu regions protein. One construct contains three mutations at epitope anti-phospho-tau antibody AT8 (AT8-3E tau), whereas four PHF1 (PHF1-4E tau). Solid-state NMR data show both mutants form homogeneous with a single set chemical shifts. AT8-3E rigid core extends from R3 repeat C terminus, PHF1-4E spans R2, R3, R4 repeats. Cryoelectron microscopy forms triangular multi-layered core, triple-stranded core. Interestingly, combining all seven exhibits same conformation as tau. Scalar-coupled additionally reveal dynamics shape fuzzy coat surrounding cores. These results demonstrate specific PTMs structurally aggregates, code redundancy.

Язык: Английский

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Selective Detection of Intermediate-Amplitude Motion by Solid-State NMR

The Journal of Physical Chemistry B, Год журнала: 2024, Номер 128(10), С. 2293 - 2303

Опубликована: Фев. 28, 2024

The coexistence of rigid and mobile molecules or molecular segments abounds in biomolecular assemblies. Examples include the carbohydrate-rich cell walls plants intrinsically disordered proteins that contain β-sheet cores. In solid-state nuclear magnetic resonance (NMR) spectroscopy, dipolar polarization transfer experiments are well suited for detecting components, whereas scalar-coupling highly components. However, few NMR methods available to detect undergo intermediate-amplitude fast motion. Here, we introduce two experiments, a two-dimensional T2H-filtered CP-hCH correlation three-dimensional J-INADEQUATE CCH correlation, observe this Both involve 1H detection under magic-angle spinning (MAS). By combining transverse relaxation (T2H) filters with transfer, suppress signals both species, thus revealing intermediate species. MAS is crucial distinguishing different motional amplitudes. We demonstrate these techniques on several plant wall samples show they allow selective resolution certain hemicellulose pectin signals, which usually masked by cellulose dynamic pectins purely scalar spectra.

Язык: Английский

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A review on traditional Chinese medicine natural products and acupuncture intervention for Alzheimer’s disease based on the neuroinflammatory

Chinese Medicine, Год журнала: 2024, Номер 19(1)

Опубликована: Фев. 28, 2024

Abstract Alzheimer’s disease (AD) is a neurodegenerative with insidious onset and progressive development. It clinically characterized by cognitive impairment, memory impairment behavioral change. Chinese herbal medicine acupuncture are important components of traditional (TCM), commonly used in clinical treatment AD. This paper systematically summarizes the research progress natural products AD, which combined existing preclinical evidence, based on comprehensive review neuroinflammation, discusses efficacy potential mechanisms Resveratrol, curcumin, kaempferol other can significantly inhibit neuroinflammation AD vivo vitro, candidates for Acupuncture alleviate improving synaptic plasticity, nerve cell apoptosis reducing production aggregation amyloid β protein (Aβ) brain. has characteristics early, safe, effective benign bidirectional adjustment. The purpose this to provide basis strategies TCM Graphical

Язык: Английский

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α-synuclein and tau: interactions, cross-seeding, and the redefinition of synucleinopathies as complex proteinopathies

Frontiers in Neuroscience, Год журнала: 2025, Номер 19

Опубликована: Март 27, 2025

Neurodegenerative diseases are characterized by protein aggregation and overlapping pathologies, challenging traditional classifications highlighting shared underlying mechanisms. Parkinson’s disease related synucleinopathies, including Lewy body dementia multiple system atrophy, highlight the interplay between α-synuclein tau, two key proteins implicated in these disorders. Recent studies reveal that tau co-aggregate, interact synergistically, propagate via prion-like mechanisms, exacerbating neuronal dysfunction. This review examines physiological roles pathological transitions of α-synuclein, emphasizing their microtubule dynamics, synaptic regulation, structural heterogeneity aggregates. Evidence from post-mortem brains, transgenic models, proteomic analyses underscores significance soluble oligomers as primary neurotoxic species explores diverse molecular composition bodies glial cytoplasmic inclusions. The co-localization influenced genetic factors post-translational modifications, offers insights into mechanisms across synucleinopathies tauopathies. These findings advocate for integrated therapeutic strategies targeting cross-seeding proteostatic disruption while preserving roles. By framing neurodegeneration a collapse networks rather than isolated proteinopathies, this work proposes paradigm shift toward understanding treating complex neurodegenerative

Язык: Английский

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Nature's toolbox against tau aggregation: An updated review of current research

Ageing Research Reviews, Год журнала: 2023, Номер 87, С. 101924 - 101924

Опубликована: Март 31, 2023

Язык: Английский

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Membrane-induced tau amyloid fibrils

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Апрель 28, 2023

The intrinsically disordered protein tau aggregates into β-sheet amyloid fibrils that spread in human brains afflicted with Alzheimer's disease and other neurodegenerative diseases. Tau interaction lipid membranes might play a role the formation spreading of these pathological aggregates. Here we investigate conformation assembly membrane-induced using solid-state NMR transmission electron microscopy. A construct encompasses microtubule-binding repeats proline-rich domain is reconstituted cholesterol-containing phospholipid membranes. 2D 13C-13C correlation spectra indicate converted from random coil to over weeks. Small unilamellar vesicles (SUVs) cause different equilibrium conformations large (LUVs) multilamellar (MLVs). Importantly, SUV-bound developed long exhibit characteristic chemical shifts Tyr310 heparin-fibrillized tau. In comparison, LUVs MLVs do not induce but Lipid-protein reside at membrane-water interface, without inserting middle bilayer. Removal cholesterol SUVs abolished fibrils, indicating both membrane curvature are required for fibril formation. These results have implications how nucleate

Язык: Английский

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Super-resolution imaging unveils the self-replication of tau aggregates upon seeding

Cell Reports, Год журнала: 2023, Номер 42(7), С. 112725 - 112725

Опубликована: Июль 1, 2023

Tau is a soluble protein interacting with tubulin to stabilize microtubules. However, under pathological conditions, it becomes hyperphosphorylated and aggregates, process that can be induced by treating cells exogenously added tau fibrils. Here, we employ single-molecule localization microscopy resolve the aggregate species formed in early stages of seeded aggregation. We report entry sufficient assemblies into cytosol induces self-replication small doubling time 5 h inside HEK 1 day murine primary neurons, which then grow Seeding occurs vicinity microtubule cytoskeleton, accelerated proteasome, results release media. In absence seeding, still spontaneously form aggregates at lower levels. Overall, our work provides quantitative picture templated aggregation cells.

Язык: Английский

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