Multi-target-directed therapeutic strategies for Alzheimer’s disease: controlling amyloid-β aggregation, metal ion homeostasis, and enzyme inhibition

Chemical Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

This review highlights the potential of multi-target-directed strategies that address amyloid-β aggregation, metal ion dyshomeostasis, and enzyme dysfunction, offering a comprehensive effective approach to treating Alzheimer's disease.

Язык: Английский

---

The impact of genetic variability on Alzheimer’s therapies: obstacles for pharmacogenetic progress

Expert Opinion on Drug Metabolism & Toxicology, Год журнала: 2025, Номер unknown, С. 1 - 28

Опубликована: Янв. 21, 2025

Genetic load influences the therapeutic response to conventional drugs in Alzheimer's disease (AD). Pharmacogenetics (PGx) is best option reduce drug-drug interactions and adverse drug reactions patients undergoing polypharmacy regimens. However, there are important limitations that make it difficult incorporate pharmacogenetics into routine clinical practice. This article analyzes pharmacogenetic apparatus made up of pathogenic, mechanistic, metabolic, transporter, pleiotropic genes responsible for efficacy safety pharmacological treatment, impact genetic on outcome multifactorial treatments, practical aspects effective use PGx. Over 120 closely associated with AD. There an accumulation cerebrovascular (CVn) neurodegenerative (ADn) APOE-4 carriers accumulate more deleterious related other CVn ADn genes, develop earlier, at a biological disadvantage compared non-carriers. CYP2D6-PMs worst responders anti-dementia drugs. Some hinder implementation PGx practice, including lack information many drugs, low number screening protocols, educational deficiencies medical community regarding genomic medicine.

Язык: Английский

---

Increasing brain half-life of antibodies by additional binding to myelin oligodendrocyte glycoprotein, a CNS specific protein

Fluids and Barriers of the CNS, Год журнала: 2025, Номер 22(1)

Опубликована: Янв. 30, 2025

Therapeutic antibodies for the treatment of neurological disease show great potential, but their applications are rather limited due to brain exposure. The most well-studied approach enhance influx protein therapeutics, is receptor-mediated transcytosis (RMT) by targeting nutrient receptors shuttle therapeutics over blood–brain barrier (BBB) along with endogenous cargos. While higher exposure achieved RMT, timeframe short fast clearance. Therefore, we aim increase half-life binding myelin oligodendrocyte glycoprotein (MOG), a CNS specific protein. Alpaca immunization mouse/human MOG, and subsequent phage selections screenings MOG single variable domain (VHHs) were performed find cross-reactive VHHs. Their ability was evaluated in healthy wild-type mice coupling two different VHHs (low/high affinity) mono- bivalent format β-secretase 1 (BACE1) inhibiting antibody or control (anti-SARS-CoV-2) antibody, fused an anti-transferrin receptor (TfR) VHH active transport BBB. Brain pharmacokinetics pharmacodynamics, peripheral biodistribution, toxicity after intravenous administration balb/c mice. Additional increases Cmax that actively shuttled Anti-SARS-CoV-2 coupled anti-TfR low affinity anti-MOG could be detected 49 days injection, which major improvement compared anti-SARS-CoV-2 cannot anymore one week post treatment. does not affect biodistribution alters distribution white matter localization less neuronal internalization. We have discovered mouse/human/cynomolgus drastically antibodies. Combining TfR leads distinct PK, exposure, differentiating it from highly investigated TfR-shuttling. It first time such long has been demonstrated dose. This new adding moiety targets RMT shuttling huge advancement field paves way further research into extension.

Язык: Английский

---

Tangeretin offers neuroprotection against colchicine-induced memory impairment in Wistar rats by modulating the antioxidant milieu, inflammatory mediators and oxidative stress in the brain tissue

BMC Complementary Medicine and Therapies, Год журнала: 2025, Номер 25(1)

Опубликована: Фев. 4, 2025

Язык: Английский

---

Is Australia ready for the rollout of amyloid‐targeting therapies for Alzheimer's disease? Results from a national survey characterising current infrastructure capability, workforce and training needs of memory and cognition clinics

Internal Medicine Journal, Год журнала: 2025, Номер unknown

Опубликована: Фев. 6, 2025

Abstract Background New amyloid‐targeting monoclonal antibody (mAb) therapies for Alzheimer's disease (AD) are currently under review by the Therapeutic Goods Administration use in Australia. Aims To determine infrastructure, workforce and training needs of Australian memory cognition clinics order to characterise health system preparedness these therapies. Methods A national, cross‐sectional online survey medical specialists. Results Thirty specialists (geriatricians, n = 23; psychiatrists, 4; neurologists, 3) from 30 different participated (public, 76.7%; private, 23.3%), including metropolitan (73.3%), regional (20.0%) rural (6.7%) areas. On average, reported assessing 5.4 (SD 3.2) new patients per week, which 2.4 (range: 0–5) were considered have mild cognitive impairment (MCI). Only 40% biomarkers assess whether with MCI AD, 45% intravenous infusion capability. While majority clinicians confident their knowledge mAbs, only 33% felt using these. Identified impediments clinical implementation included (i) lack real‐world experience, (ii) current Models Care appropriate guidelines, (iii) clinic set‐up (iv) information about safety. Conclusions Australia's mAb will require further investment equity access, clinician support. Long wait times already impact access clinics, forecast rise dementia cases, services need be expanded, clear efficient inter‐sector pathways needed prepare mAbs.

Язык: Английский

---

The Common Alzheimer's Disease Research Ontology (CADRO) for biomarker categorization

Alzheimer s & Dementia Translational Research & Clinical Interventions, Год журнала: 2025, Номер 11(1)

Опубликована: Янв. 1, 2025

Язык: Английский

---

Allogeneic mesenchymal stem cell therapy with laromestrocel in mild Alzheimer’s disease: a randomized controlled phase 2a trial

Nature Medicine, Год журнала: 2025, Номер unknown

Опубликована: Март 10, 2025

Abstract Alzheimer’s disease (AD) is characterized by progressive cognitive decline, severe brain atrophy and neuroinflammation. We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 2a clinical trial that tested the safety efficacy of laromestrocel, bone-marrow-derived, allogeneic mesenchymal stem-cell therapy, in slowing AD progression, Participants across ten centers United States were randomly assigned 1:1:1:1 to four infusion groups: group 1 (placebo; monthly infusions, n = 12); 2 (25 million cells, one followed three infusions placebo, 13); 3 cells; doses, 4 (100 11). The study met its primary end point safety; rate treatment-emergent serious adverse events within weeks any was similar all 1, 0% (95% CI 0–26.5%); 2, 7.7% 0.2–36%); 3, 0.2–36%) 4, 9.1% 0.2–41.3%). Additionally, there no reported infusion-related reactions, hypersensitivities or amyloid-related imaging abnormalities. Laromestrocel improved assessments at 39 compared as measured composite score (secondary met: versus placebo change: 0.38; 95% −0.06–0.82), Montreal assessment Disease Cooperative Study Activities Daily Living. At weeks, slowed decline whole volume ( 10) 48.4% for treatment groups combined (groups 2–4: P 0.005; 32) left hippocampal 61.9% 2–4, 0.021; 32), reduced neuroinflammation diffusion tensor imaging. change bilateral correlated with mini-mental state exam scores R 0.41, 0.0075) patients N 42). Collectively these results support single multiple doses laromestrocel mild provide indications combating potentially function. Larger-scale trials are warranted. ClinicalTrials.gov registration: NCT05233774 .

Язык: Английский

---

Comparison of Deuterium Metabolic Imaging with FDG PET in Alzheimer Disease

Radiology, Год журнала: 2025, Номер 315(1)

Опубликована: Апрель 1, 2025

Deuterium metabolic imaging was highly aligned with fluorodeoxyglucose PET in participants Alzheimer disease (AD) but unable to help differentiate AD from age-matched controls.

Язык: Английский

---

Liposome-Derived Nanosystems for the Treatment of Behavioral and Neurodegenerative Diseases: The Promise of Niosomes, Transfersomes, and Ethosomes for Increased Brain Drug Bioavailability

Pharmaceuticals, Год журнала: 2023, Номер 16(10), С. 1424 - 1424

Опубликована: Окт. 8, 2023

Psychiatric and neurodegenerative disorders are amongst the most prevalent debilitating diseases, but current treatments either have low success rates, greatly due to permeability of blood–brain barrier, and/or connected severe side effects. Hence, new strategies extremely important, here is where liposome-derived nanosystems come in. Niosomes, transfersomes, ethosomes nanometric vesicular structures that allow drug encapsulation, protecting them from degradation, increasing their solubility, permeability, brain targeting, bioavailability. This review highlighted great potential these for treatment Alzheimer’s disease, Parkinson’s schizophrenia, bipolar disorder, anxiety, depression. Studies regarding encapsulation synthetic natural-derived molecules in systems, intravenous, oral, transdermal, or intranasal administration, led an increased bioavailability when compared conventional pharmaceutical forms. Moreover, developed formulations proved neuroprotective, anti-inflammatory, antioxidant effects, including neurotransmitter level restoration oxidative status improvement, improved locomotor activity enhancement recognition working memories animal models. albeit being relatively technologies, niosomes, already proven increase psychoactive drugs, leading effectiveness decreased showing promise as future therapeutics.

Язык: Английский

---

Astaxanthin enhances autophagy, amyloid beta clearance and exerts anti-inflammatory effects in in vitro models of Alzheimer’s disease-related blood brain barrier dysfunction and inflammation

Brain Research, Год журнала: 2023, Номер 1819, С. 148518 - 148518

Опубликована: Авг. 12, 2023

Defective degradation and clearance of amyloid-β as well inflammation per se are crucial players in the pathology Alzheimer's disease (AD). A defective transport across blood-brain barrier is causative for (Aβ) accumulation brain, provoking amyloid plaque formation. Using primary porcine brain capillary endothelial cells murine organotypic hippocampal slice cultures vitro models AD, we investigated effects antioxidant astaxanthin (ASX) on Aβ neuroinflammation. We report that ASX enhanced misfolded proteins by inducing autophagy altered processing pathway. observed a reduction expression levels intracellular secreted precursor protein/Aβ accompanied an increase ABC transporters ABCA1, ABCG1 low density lipoprotein receptor-related protein 1 mRNA levels. Furthermore, treatment increased autophagic flux evidenced lipidation LC3B-II reduced phosphorylated S6 ribosomal mTOR. In LPS-stimulated slices, exerted anti-inflammatory reducing secretion inflammatory cytokines while shifting microglia polarization from M1 to M2 phenotype. Our data suggest potential therapeutic compound ameliorating AD-related blood impairment inflammation.

Язык: Английский

---