Recent advancement in understanding of Alzheimer's disease: Risk factors, subtypes, and drug targets and potential therapeutics

Ageing Research Reviews, Год журнала: 2024, Номер 101, С. 102476 - 102476

Опубликована: Авг. 31, 2024

Язык: Английский

---

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

---

Efficacy of Communication Bridge‐2 for primary progressive aphasia: A randomized controlled trial of communication intervention

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(3)

Опубликована: Март 1, 2025

Abstract INTRODUCTION Primary progressive aphasia (PPA), a language‐based neurodegenerative dementia, negatively impacts communication and quality of life. Previous non‐pharmacologic interventions show promise but lack efficacy trials. Here, outcomes are provided from Communication Bridge‐2 (CB2), speech‐language randomized controlled trial (RCT) for PPA. METHODS CB2 is the first Phase 2, Stage II, parallel‐group RCT delivered via video chat with global enrollment. Ninety‐five dyads were into one two intervention arms. included confidence participation measures. Marginal linear models assessed across ≈12 months. RESULTS four countries. Experimental arm superiority in communication‐participation measurement goal attainment was demonstrated (66.7% vs 49.1%, respectively, p = 0.006), corroborated by post‐study interviews. DISCUSSION Outcomes demonstrate feasibility initial person‐centered telemedicine maximizing mild‐to‐moderate PPA, providing pathway developing implementing clinically meaningful Alzheimer's disease related dementias. Highlights (PPA) participation. (CB2) telemedicine‐delivered (RCT). Global recruitment 95 PPA participant an low dropout. First international using shows efficacy. The study provides model rigorous trials disease/Alzheimer's dementias (AD/ADRD).

Язык: Английский

---

Low-Density Lipoprotein Receptor-Related Protein 1 as a Potential Therapeutic Target in Alzheimer’s Disease

Pharmaceutics, Год журнала: 2024, Номер 16(7), С. 948 - 948

Опубликована: Июль 17, 2024

Alzheimer’s disease (AD) is a progressive neurodegenerative impacting the lives of millions people worldwide. The formation amyloid β (Aβ) plagues in brain main pathological hallmark AD. Aβ deposits are formed due to imbalance between production and clearance across blood–brain barrier (BBB). In this respect, low-density lipoprotein receptor-related protein 1 (LRP1) plays significant role by mediating both clearance. Due its important AD pathogenesis, LRP1 considered an attractive drug target for therapies. present review, we summarize current knowledge about pathogenesis as well recent findings on changes expression function Finally, discuss advances utilizing treatments future perspectives research.

Язык: Английский

---

O-GlcNAc modification differentially regulates microtubule binding and pathological conformations of tau isoforms in vitro

Journal of Biological Chemistry, Год журнала: 2025, Номер 301(3), С. 108263 - 108263

Опубликована: Фев. 3, 2025

Язык: Английский

---

Mitochondrial Calcium Uniporter knockdown improves the viability of HT22 hippocampal neurons in Alzheimer’s disease

European Journal of Pharmacology, Год журнала: 2025, Номер unknown, С. 177347 - 177347

Опубликована: Фев. 1, 2025

Язык: Английский

---

Therapeutic Treatment With OLX‐07010 Inhibited Tau Aggregation and Ameliorated Motor Deficits in an Aged Mouse Model of Tauopathy

Journal of Neurochemistry, Год журнала: 2025, Номер 169(3)

Опубликована: Март 1, 2025

Targeting tau protein is a strategy for the development of disease-modifying therapeutics Alzheimer's disease (AD) and numerous rare tauopathies. A small molecule approach targeting aggregation was used to select optimize compounds inhibiting self-association in vitro that have translated vivo preventive studies htau P301L JNPL3 mouse models tauopathy. In this therapeutic treatment study, aged mice with pre-existing aggregates were evaluate effect OLX-07010. The study had Baseline group 7 months, vehicle, two dose groups treated until 12 months by administration feed. primary endpoint reduction insoluble statistical significance. secondary endpoints dose-dependent aggregates, soluble tau, improvement motor behavior. ELISAs immunoblots determine levels its aggregated forms including self-associated Sarkosyl tau. Effect on behavior, as measured Rotarod assay, also assessed between groups. At end treatment, reduced overall heat-stable fraction significance cortex observed. Treatment prevented accumulation above baseline, parallel, improved behavior assay compared baseline vehicle control groups, suggesting rescuing impairment mice. functional biochemical readouts suggest has potential treating neurodegenerative diseases characterized such AD progressive supranuclear palsy.

Язык: Английский

---

Pilot Study for Deciphering Post-Translational Modifications and Proteoforms of Tau Protein by Capillary Electrophoresis-Mass Spectrometry

Journal of Proteome Research, Год журнала: 2024, Номер unknown

Опубликована: Сен. 27, 2024

Abnormal accumulation of tau protein in the brain is one pathological hallmark Alzheimer's disease (AD). Many post-translational modifications (PTMs) are associated with development AD, such as phosphorylation, acetylation, and methylation. Therefore, a complete picture PTM landscape critical for understanding molecular mechanisms AD progression. Here, we offered pilot study combining two complementary analytical techniques, capillary zone electrophoresis (CZE)-tandem mass spectrometry (MS/MS) reversed-phase liquid chromatography (RPLC)-MS/MS, bottom-up proteomics recombinant human tau-0N3R. We identified 50 phosphorylation sites tau-0N3R total, which about 25% higher than that from RPLC-MS/MS alone. CZE-MS/MS provided more (i.e., phosphorylation) modified peptides RPLC-MS/MS, its predicted electrophoretic mobility helped improve confidence peptides. developed highly efficient isoelectric focusing (cIEF)-MS technique to offer bird's-eye view proteoforms, 11 putative proteoforms carrying up nine lower pI values phosphorylated detected. Interestingly, under native-like cIEF-MS conditions, observed three dimers phosphate groups. The findings demonstrate CE-MS valuable characterization PTMs, even oligomerization.

Язык: Английский

---

From Plaques to Pathways in Alzheimer’s Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(21), С. 11720 - 11720

Опубликована: Окт. 31, 2024

Alzheimer's disease (AD) presents a public health challenge due to its progressive neurodegeneration, cognitive decline, and memory loss. The amyloid cascade hypothesis, which postulates that the accumulation of amyloid-beta (Aβ) peptides initiates leading AD, has dominated research therapeutic strategies. failure recent Aβ-targeted therapies yield conclusive benefits necessitates further exploration AD pathology. This review proposes Mitochondrial-Neurovascular-Metabolic (MNM) integrates mitochondrial dysfunction, impaired neurovascular regulation, systemic metabolic disturbances as interrelated contributors pathogenesis. Mitochondrial hallmark leads oxidative stress bioenergetic failure. Concurrently, breakdown blood-brain barrier (BBB) cerebral blood flow, characterize dysregulation, accelerate neurodegeneration. Metabolic such glucose hypometabolism insulin resistance impair neuronal function survival. hypothesis highlights interconnectedness these pathways suggests strategies targeting health, integrity, regulation may offer more effective interventions. MNM addresses multifaceted aspects providing comprehensive framework for understanding progression developing novel approaches. approach paves way innovative could significantly improve outcomes millions affected worldwide.

Язык: Английский

---

Communication Bridge‐2 randomized controlled trial: Recruitment and baseline features

Alzheimer s & Dementia, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 26, 2024

Abstract INTRODUCTION Non‐pharmacological interventions may offer significant benefits to the quality of life for persons with primary progressive aphasia (PPA) and their care partners but have lacked efficacy trials. To help fill gap, we provide feasibility recruitment, enrollment, randomization, baseline data Communication Bridge‐2 (CB2) randomized controlled trial (RCT). METHODS CB2 is first international, single enrollment site, Phase 2, Stage parallel‐group, active control, RCT delivered via video chat individuals PPA partners. Participants were recruited, screened, into one two speech–language intervention arms. RESULTS Ninety‐five participant dyads (PPA mean age: 67.1; 48% female) from four countries enrolled randomized. DISCUSSION Global randomization a chat–delivered non‐pharmacologic feasible. This provides potential model conducting rigorous trials Alzheimer's disease related dementias. Highlights Primary negatively impacts communication participation. telemedicine‐delivered trial. included global recruitment 95 dyads. CB2, international superiority using shows feasibility. The study

Язык: Английский

---