Nature Mental Health, Год журнала: 2024, Номер 2(1), С. 25 - 40
Опубликована: Янв. 10, 2024
Язык: Английский
Ageing Research Reviews, Год журнала: 2021, Номер 72, С. 101496 - 101496
Опубликована: Окт. 22, 2021
Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.
Язык: Английский
Процитировано
219
FEBS Journal, Год журнала: 2022, Номер 290(6), С. 1420 - 1453
Опубликована: Янв. 8, 2022
Alzheimer’s disease (AD) is an age‐associated neurodegenerative disorder with multifactorial etiology, intersecting genetic and environmental risk factors, a lack of disease‐modifying therapeutics. While the abnormal accumulation lipids was described in very first report AD neuropathology, it not until recent decades that lipid dyshomeostasis became focus research. Clinically, lipidomic metabolomic studies have consistently shown alterations levels various classes emerging early stages brains. Mechanistically, discovery research revealed multifaceted interactions between metabolism key pathogenic mechanisms including amyloidogenesis, bioenergetic deficit, oxidative stress, neuroinflammation, myelin degeneration. In present review, converging evidence defining summarized, followed by discussions on which contributes to pathogenesis modifies risk. Furthermore, lipid‐targeting therapeutic strategies, modification their efficacy stage, ApoE status, metabolic vascular profiles, are reviewed.
Язык: Английский
Процитировано
184
Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)
Опубликована: Авг. 23, 2024
Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.
Язык: Английский
Процитировано
129
Trends in Neurosciences, Год журнала: 2022, Номер 45(5), С. 401 - 414
Опубликована: Фев. 17, 2022
Язык: Английский
Процитировано
88
Biomolecules, Год журнала: 2022, Номер 12(1), С. 129 - 129
Опубликована: Янв. 14, 2022
Alzheimer's disease (AD) is the most common form of dementia in elderly population, affecting over 55 million people worldwide. Histopathological hallmarks this multifactorial are an increased plaque burden and tangles brains affected individuals. Several lines evidence indicate that B12 hypovitaminosis linked to AD. In review, biochemical pathways involved AD by vitamin B12, focusing on APP processing, Aβ fibrillization, Aβ-induced oxidative damage as well tau hyperphosphorylation aggregation, summarized. Besides mechanistic link, overview clinical studies utilizing B supplementation given, a potential link between diseases medication resulting reduced level discussed. disease-mediated hypovitaminosis, reduction levels caused increasing change dietary preferences has been gaining relevance. particular, vegetarian vegan diets associated with deficiency, therefore might have implications for conclusion, our review emphasizes important role AD, which particularly important, even industrialized countries large proportion population not be sufficiently supplied B12.
Язык: Английский
Процитировано
78
Nutrients, Год журнала: 2022, Номер 14(21), С. 4564 - 4564
Опубликована: Окт. 30, 2022
Alzheimer’s disease is a progressive brain that becoming major health problem in today’s world due to the aging population. Despite it being widely known diet has significant impact on prevention and progression of disease, literature data are still scarce controversial. The application principles rational nutrition for elderly suggested disease. should be rich neuroprotective nutrients, i.e., antioxidants, B vitamins, polyunsaturated fatty acids. Some studies suggest diets such as Mediterranean diet, DASH (Dietary Approaches Stop Hypertension) MIND (Mediterranean-DASH Intervention Neurodegenerative Delay) have beneficial effect risk developing
Язык: Английский
Процитировано
78
Nature Communications, Год журнала: 2024, Номер 15(1)
Опубликована: Март 12, 2024
Abstract Developing diagnostics and treatments for neurodegenerative diseases (NDs) is challenging due to multifactorial pathogenesis that progresses gradually. Advanced in vitro systems recapitulate patient-like pathophysiology are emerging as alternatives conventional animal-based models. In this review, we explore the interconnected pathogenic features of different types ND, discuss general strategy modelling NDs using a microfluidic chip, introduce organoid-on-a-chip next advanced relevant model. Lastly, overview how these models being applied academic industrial drug development. The integration chips, stem cells, biotechnological devices promises provide valuable insights biomedical research developing diagnostic therapeutic solutions NDs.
Язык: Английский
Процитировано
26
Pharmaceutics, Год журнала: 2022, Номер 14(4), С. 835 - 835
Опубликована: Апрель 11, 2022
Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. Most existing treatments only provide symptomatic solutions. Here, we introduce currently available commercial drugs new therapeutics, including repositioned drugs, to treat AD. Despite tremendous efforts, targeting the hallmarks of AD show limited efficacy. Challenges in treating are partly caused by difficulties penetrating blood-brain barrier (BBB). Recently, nanoparticle (NP)-based systems have shown promising potential as precision medicines that can effectively penetrate BBB enhance ability numerous drugs. describe how NPs enter brain crossing, avoiding, or disrupting BBB. In addition, overview action microenvironment for treatment Diverse systems, liposomes, micelles, polymeric NPs, solid-lipid inorganic been investigated NP drug loading relieve symptoms, target hallmarks, moieties diagnose We also highlight NP-based immunotherapy, which has recently gained special attention a option disrupt progression. Overall, this review focuses on represent innovative strategies understand pathogenesis suggests diagnostic modalities cure
Язык: Английский
Процитировано
62
Acta Neuropathologica Communications, Год журнала: 2023, Номер 11(1)
Опубликована: Апрель 26, 2023
Abstract Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in brain and to study Alzheimer’s disease (AD). We performed a genome-wide association on largest collection data (N = 13,409) date, across multiple ethnicities from multicenter cohorts identify variants associated with amyloidosis AD risk. found strong APOE signal chr19q.13.32 (top SNP: ɛ4; rs429358; β 0.35, SE 0.01, P 6.2 × 10 –311 , MAF 0.19), driven by ɛ4, five additional novel associations ( ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, rs4420638) independent ɛ4. ɛ4 ε2 showed race specific effect stronger Non-Hispanic Whites, lowest Asians. Besides we also identified three other loci: ABCA7 (rs12151021/chr19p.13.3; 0.07, 9.2 –09 0.32), CR1 (rs6656401/chr1q.32.2; 0.1, 0.02, 2.4 –10 0.18) FERMT2 locus (rs117834516/chr14q.22.1; 0.16, 0.03, 1.1 0.06) that all colocalized Sex-stratified analyses two female-specific signals chr5p.14.1 (rs529007143, 0.79, 0.14, 1.4 –08 0.006, sex-interaction 9.8 –07 ) chr11p.15.2 (rs192346166, 0.94, 0.17, 3.7 0.004, 1.3 –03 ). demonstrated overall genetic architecture overlaps AD, Frontotemporal Dementia, stroke, structure-related complex human traits. Overall, our results have important implications when estimating individual risk population level, as sex will needed be taken into account. This may affect participant selection future clinical trials therapies.
Язык: Английский
Процитировано
30
Progress in Lipid Research, Год журнала: 2023, Номер 90, С. 101225 - 101225
Опубликована: Март 31, 2023
Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation the underlying mechanisms and development efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) Niemann-Pick type C disease (NPCD) caused by specific variants sphingomyelin phosphodiesterase 1 (SMPD1) NPC intracellular cholesterol transporter (NPC1) or 2 (NPC2) genes that perturb key membrane components, cholesterol, respectively. Patients with severe forms these present visceral neurologic symptoms succumb premature death. This synopsis traces tortuous discovery diseases, highlights important advances respect genetic culprits cellular mechanisms, exposes efforts improve diagnosis explore new therapeutic approaches.
Язык: Английский
Процитировано
28