Biomedicine & Pharmacotherapy, Год журнала: 2025, Номер 183, С. 117815 - 117815
Опубликована: Янв. 15, 2025
Язык: Английский
The Journal of Prevention of Alzheimer s Disease, Год журнала: 2025, Номер unknown, С. 100150 - 100150
Опубликована: Март 1, 2025
Язык: Английский
Процитировано
1
Biomolecules, Год журнала: 2024, Номер 14(7), С. 833 - 833
Опубликована: Июль 11, 2024
Microglia, as resident macrophages in the central nervous system, play a multifunctional role pathogenesis of Alzheimer’s disease (AD). Their clustering around amyloid-β (Aβ) deposits is core pathological feature AD. Recent advances single-cell RNA sequencing (scRNA-seq) and single-nucleus (snRNA-seq) have revealed dynamic changes microglial phenotypes over time across different brain regions during aging AD progression. As advances, microglia primarily exhibit impaired phagocytosis Aβ tau, along with release pro-inflammatory cytokines that damage synapses neurons. Targeting has emerged potential therapeutic approach for Treatment strategies involving can be broadly categorized into two aspects: (1) enhancing function: This involves augmenting their phagocytic ability against cellular debris (2) mitigating neuroinflammation: Strategies include inhibiting TNF-α signaling to reduce neuroinflammatory response triggered by microglia. Clinical trials exploring microglia-related approaches treatment garnered attention. Additionally, natural products show promise beneficial effects suppressing inflammatory responses. Clarifying dynamics, understanding roles, novel will advance our fight
Язык: Английский
Процитировано
7
Biomaterials, Год журнала: 2024, Номер 312, С. 122749 - 122749
Опубликована: Авг. 6, 2024
Язык: Английский
Процитировано
7
Chinese Journal of Natural Medicines, Год журнала: 2024, Номер 22(8), С. 699 - 710
Опубликована: Авг. 1, 2024
Язык: Английский
Процитировано
7
Alzheimer s & Dementia, Год журнала: 2024, Номер unknown
Опубликована: Сен. 6, 2024
Abstract BACKGROUND The Mnemonic Similarity Task (MST) is a popular memory task designed to assess hippocampal integrity. We assessed whether analyzing MST performance using multinomial processing tree (MPT) cognitive model could detect individuals with elevated Alzheimer's disease (AD) biomarker status prior decline. METHOD analyzed data from >200 (young, cognitively healthy older adults and mild impairment [MCI]), subset of which also had existing cerebrospinal fluid (CSF) amyloid beta (Aβ) phosphorylated tau (pTau) both traditional model‐derived approaches. how well each predict age group, ability, MCI status, Aβ, pTau receiver operating characteristic analyses. RESULTS Both approaches predicted group membership equally, but MPT‐derived metrics exceeded in all other comparisons. DISCUSSION A MPT the can AD decline, making it potentially useful tool for screening monitoring during asymptomatic phase AD. Highlights MST, along modeling, identifies deficits impairment. Cognitive modeling increased biomarkers changes function. digital that at high risk
Язык: Английский
Процитировано
6
Neural Regeneration Research, Год журнала: 2024, Номер 19(11), С. 2343 - 2344
Опубликована: Март 8, 2024
Alzheimer's disease (AD) is the most prevalent form of dementia, i.e., progressive memory loss and profound cognitive dysfunction, resulting in a considerable societal burden. At neuropathological level, brains AD patients exhibit amyloid-β (Aβ) plaques, neurofibrillary tangles, neuroinflammation (Sala Frigerio De Strooper, 2016). The growing number individuals affected with underscores pressing need for development effective treatments, cure remains elusive. pathogenesis involves intricate molecular cellular mechanisms that lead to neurodegeneration decline. A central tenet amyloid cascade hypothesis, which posits accumulation Aβ peptides plays pivotal role progression. derives from precursor protein (APP) by BACE1 (β-secretase) γ-secretase cleavages, aggregates into plaques eventually disrupt neuronal function. Concurrently, abnormal phosphorylation tau leads formation contributing degeneration. Neuroinflammation, oxidative stress, mitochondrial synaptic impairment further compound pathology interplay these phenomena challenges treating AD, necessitating innovative therapeutic approaches halt or slow progression effectively. Recently, monoclonal antibody drugs, like Aducanumab, Lecanemab, Donanemab, have shown ability decelerate decline phase III clinical trials early-stage (Boxer Sperling, 2023). Aducanumab designed bind both oligomeric fibrillar states rather than monomers, while Lecanemab has been proposed target so called protofibrils. Donanemab directed against N-terminally modified Aβ. These collectively suggest approach represents an strategy particularly its early stages. While drugs gained significant attention their effects mitigating deterioration several crucial aspects warrant consideration, including (1) Efficacy side effects: antibodies do play slowing magnitude efficacy may vary, benefits be weighed probability This importance thorough assessment potential drawbacks drugs. (2) Blood-brain barrier permeability: compounds faces notable failure rate, many tested compounds, antibodies, exhibiting poor permeability across blood-brain barrier. limitation poses obstacle nervous system disorders emphasizes enhance drug delivery. (3) Late-stage treatment: typically diagnosed later stages, characterized observable impairment. It unclear whether same highlights necessity treatment strategies take account evolving nature disease. (4) Multifactorial AD: recognized as contributor but it probably not sole driving force, factors pathology, neuro-inflammation, stress also integral roles. Thus, there acknowledgment develop interventions comprehensively multifactorial AD. Molecular chaperones preserving homeostasis (proteostasis). ATP-independent chaperones, often referred "holdases", maintain (partially) unfolded client proteins folding-competent state without necessarily refolding them, leaving task degradation other systems. Experimental data small heat shock (sHsps), can prevent resolve aggregation neurodegenerative diseases For instance, Hsp27 (HspB1) impedes fibrils engaging weak interactions species during process, mitigates toxicity oligomers sequestering them transforming larger, non-toxic (Wentink et al., 2019). αB-crystallin (HspB5) binds wildtype Aβ42 formed Aβ42E22G (Arctic) mutant subsequently inhibits fibril Further, Nuclebindin-1 (NUCB1), identified novel chaperone-like amyloid-binding protein, demonstrates inhibitory on islet polypeptide (IAPP) linked type 2 diabetes, α-synuclein associated Parkinson's disease, transthyretin V30M related familial polyneuropathy, (Bonito-Oliva 2017). In contrast, ATP-dependent assist substrates adopting native conformation ("foldases") prepare degradation. DNAJB6, member Hsp40 family, high efficiency inhibiting extracellular secretion Hsp70 protection Aβ42-induced toxicity, effectively neurotoxicity adult eyes, reducing cell death, structural integrity neurons, alleviating locomotor extending lifespan. Additionally, engineered prove preventing impairments Drosophila model majority information about centers around sHSPs primarily located intracellularly, discovery chaperone functions likely reflects chaperoning outside cell. Clusterin, major (Humphreys 1999), demonstrated inhibit disrupting nucleation process affecting elongation rate. rat brains, microinjection oligomers, pre-incubated 1 hour such clusterin α2-macroglobulin, prevents learning impairments, reduces gliosis degeneration, suppresses oligomer cytotoxicity. intracellular tau-interacting (Foster Furthermore, intraventricular infusion ameliorate cognition reduce Tg6799 (Qi 2018), peripheral administration human recombinant was able modulate brain levels APP23 mice (de Retana Interestingly, disrupted proteostasis persistent response activity are notably, chemical successfully restores mouse leading improved reduced (Hafycz findings underscore multi-targeted exist cross accumulates extracellularly senile intracellularly tangles brain, research needed optimize contrast classical BRICHOS domain, consisting approximately 100 amino acid residues, stands out anti-amyloid chaperone. present proproteins encompassing amyloid-forming region, domain thought amyloidogenic region forming (Leppert term "BRICHOS" derived initially containing this namely Bri2, chondromodulin-1, prosurfactant C. Under physiological conditions, supposedly facilitates proper folding amyloid-prone within respective proprotein, then proteolytically released (Sánchez-Pulido 2002; Chen 2022). Recent versatile broad substrate spectrum, "alien" (i.e., parts proproteins) various well bacterial functional proteins, AD-relevant Aβ40, Huntington's disease-associated huntingtin peptide, disease-linked α-synuclein, aortic peptide medin, C, de novo-designed β17 (Figure 1). IAPP, interact smallest emerging toxic oligomers. Intriguingly, efficiently reduces, rescue, hippocampal slice preparations passes wild-type models, allowing intravenous preventive formation, undergone rigorous testing 1; Leppert melanogaster fly expressing Aβ42, brain-expressed gave reduction deposition, lifespan, enhanced activity, rescued pathological eye phenotypes. Co-expression resulted shift distribution mushroom body. overexpressing APP presenilin 1, coexpression led impacting processing. Mice coexpressing exhibited compared AβPP/presenilin control animals overexpressed green fluorescent protein. knockin (APPNL-F) model, harbors Swedish (KM670/671NL) Beyreuther/Iberian (I716F) mutations develops plaque astrogliosis, microgliosis starting age 9–12 months, repeated 19 months burden cortex. With similar approach, applied 3-month APPNL-G-F addition carries Arctic mutation (E693G) AD-like features 2–4 because more aggressive recognition working decreased activation astrocytes microglia (Manchanda Recombinant administrated 10 old mice, at stage where established since long, burden, mitigated astro- microgliosis, altered gene expression. Taken together, emerges promising candidate warrants investigation through trials.Figure 1: Activities applications BRICHOS.The evaluated extensively, vitro regarding different peptides/proteins (top left); ex vivo, rescue amyloid-induced assessed electrophysiological measurements right); vivo animal fruit flies models ages (bottom panel). Specifically, interacts (unpublished data), HD-associated PD-linked FapC, β17. Notably, rescues preparations, specifically γ-oscillations. rigorously examined diverse models. includes experiments APP/PS1 birth, along APPNL-F onset occurs 15 months. intravenously 10-month (manuscript submitted) exhibits consistently mitigate neuroinflammation, memory. compelling outcomes position highly cartoon tertiary structure predicted Alphafold syringe injection tail vein. Created BioRender.com. disease; APP: protein; Aβ: amyloid-β; FapC: C; HD: IAPP: polypeptide; PD: PS1: T2D: diabetes.In summary, two primary hallmarks stemming respectively. were Aβ, BRICHOS, abilities interfere tau. superior aducanumab mechainism underlying (-like) discussed (Abelein Johansson, Further efforts treatment. work supported grants Association Research Grant (to GC), Olle Engkvists Stiftelse Petrus Augusta Hedlunds Åke Wibergs stiftelse Alzheimer foundation Åhlén Stiftelsens Karolinska Institutet Foundation Stiftelsen för Gamla Tjänarinnor Sigurd och Elsa Goljes Minne Loo Hans Osterman Geriatric Diseases Gun Bertil Stohne's Magnus Bergvall GC). C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y
Язык: Английский
Процитировано
5
Neurology, Год журнала: 2024, Номер 103(4)
Опубликована: Июль 24, 2024
Current epidemiologic data of early-onset dementia (EOD), characterized by the onset disease before age 65, are notably scarce.
Язык: Английский
Процитировано
5
Frontiers in Aging Neuroscience, Год журнала: 2024, Номер 16
Опубликована: Авг. 21, 2024
Introduction Alzheimer’s disease (AD), a major cause of dementia globally, imposes significant societal and personal costs. This review explores the efficacy physical exercise as non-pharmacological intervention to mitigate impacts AD. Methods draws on recent studies that investigate effects neuroinflammation neuronal enhancement in individuals with Results Consistent alters neuroinflammatory pathways, enhances cognitive functions, bolsters brain health among AD patients. It favorably influences activation states microglia astrocytes, fortifies integrity blood-brain barrier, attenuates gut inflammation associated These changes are substantial improvements performance indicators. Discussion The findings underscore potential integrating into comprehensive management strategies. Emphasizing necessity for further research, this advocates refinement regimens maximize their enduring benefits decelerating progression
Язык: Английский
Процитировано
5
Alzheimer s & Dementia, Год журнала: 2024, Номер 20(11), С. 8129 - 8152
Опубликована: Сен. 24, 2024
The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. primary meet the definition rare diseases in United States. There is no approved treatment for tauopathies. In this context, designing most efficient development programs to translate promising targets and treatments from preclinical studies early-phase clinical trials vital. September 2022, Rainwater Charitable Foundation convened an international expert workshop focused on translation tauopathy therapeutics through trials. Our report recommends framework principled drug companion lexicon facilitate communication focusing reproducibility achieving common elements. Topics include selection targets, drugs, biomarkers, participants, study designs. maturation pharmacodynamic biomarkers demonstrate target engagement surrogate disease crucial unmet need. HIGHLIGHTS: Experts provided (discovery trials). "5 Rights" (target, drug, biomarker, trial). Current research frontotemporal degeneration, progressive supranuclear palsy, corticobasal syndrome includes 32 (37% biologics) Tau being tested Alzheimer's disease; have large
Язык: Английский
Процитировано
5
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Март 11, 2024
Abstract AD related pathologies, such as beta-amyloid (Aβ) and phosphorylated tau (pTau), are evident decades before any noticeable decline in memory occurs. Identifying individuals during this asymptomatic phase is crucial for timely intervention. The Mnemonic Similarity Task (MST), a modified recognition task, especially relevant early screening, it assesses hippocampal integrity, region affected (both directly indirectly) the progression of disease. Further, strong inferences on underlying cognitive mechanisms that support performance task can be made using Bayesian modeling. We assessed whether analyzing MST model could detect subtle changes function biomarker status prior to overt decline. analyzed data from >200 (young, cognitively healthy older adults, with MCI), subset which also had existing CSF Aβ pTau data. Traditional scores modeling multinomial processing trees was applied each participants approaches. how well predict age group, ability, MCI status, Aβ/pTau ROC analyses. Both approaches predicted group membership equally, but exceeded traditional metrics all other comparisons. This work establishes decline, making potentially useful tool both screening monitoring adults AD.
Язык: Английский
Процитировано
4