Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 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.

Language: Английский

---

Targeting synapse function and loss for treatment of neurodegenerative diseases

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 23(1), P. 23 - 42

Published: Nov. 27, 2023

Language: Английский

---

De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: March 28, 2024

Abstract N-methyl- d -aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout central nervous system. Genetic variants GRIN genes encoding NMDAR subunits associated with a spectrum neurological disorders. The M3 transmembrane helices couple directly to agonist-binding domains form helical bundle crossing closed that occludes pore. functions as transduction element whose conformational change couples ligand binding opening an ion conducting In this study, we report functional consequences 48 de novo missense GRIN1 , GRIN2A GRIN2B alter residues helix. These were identified children neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia attention deficit hyperactivity disorder. All for which comprehensive testing was completed produce gain-of-function (28/48) compared loss-of-function (9/48); 11 had indeterminant phenotype. This supports idea key structural feature gate exists stabilize state so agonist can drive channel opening. Given most enhance gating, assessed potency FDA-approved blockers on these variant receptors. data provide new insight into structure–function relationship gate, suggest within helix gain-of-function.

Language: Английский

---

INTERCEPT-AD, a phase 1 study of intravenous sabirnetug in participants with mild cognitive impairment or mild dementia due to Alzheimer's disease

The Journal of Prevention of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: 12(1), P. 100005 - 100005

Published: Jan. 1, 2025

Soluble species of multimeric amyloid-beta including globular oligomers (AβOs) and linear protofibrils are toxic to neurons. Sabirnetug (ACU193) is a humanized monoclonal antibody, raised against soluble AβO, that has over 650-fold greater binding affinity for AβOs monomers appears have relatively little amyloid plaque. To assess safety, pharmacokinetics, exploratory measures target engagement, biomarker effects, clinical efficacy sabirnetug in participants with early symptomatic Alzheimer's disease (AD; defined as mild cognitive impairment dementia due AD). Randomized, double-blind, placebo-controlled, ascending dose first-in-human phase 1 study. Fifteen study centers the United States. Sixty-five AD. Participants received one infusion 2 mg/kg, 10 25 60 or placebo (Part A) three infusions B). Safety, tolerability, serum central engagement single multiple doses sabirnetug, cerebrospinal fluid (CSF) concentrations plaque load, determined by positron emission tomography. was generally well tolerated. A larger percentage receiving (56.3%) versus (42.9%) had at least treatment emergent adverse event, approximately 29% each group considered related drug. Most events were mild-to-moderate severity. Of 48 given five developed imaging abnormalities - edema/effusion, instance mildly participant who mg/kg. Notably, none six apolipoprotein E Ɛ4 homozygotes edema/effusion hemorrhage/hemosiderin deposition. Infusion reactions, such rash, pain, erythema, not frequent (6.3% 0.0% placebo). exposure proportional both CSF. Target drug bound CSF, shown be dependent. Over months, 25% 20% reduction plaques, respectively, observed mg/kg every four weeks two weeks. The Phase INTERCEPT-AD provided dosing, data supported design ongoing ALTITUDE-AD (NCT06335173).

Language: Английский

---

Biofluid biomarker changes following treatment with sabirnetug (ACU193) in INTERCEPT-AD, a phase 1 trial in early Alzheimer's disease

The Journal of Prevention of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown, P. 100082 - 100082

Published: Feb. 1, 2025

Language: Английский

---

The role of N-methyl-D-aspartate glutamate receptors in Alzheimer’s disease: From pathophysiology to therapeutic approaches

Progress in Neurobiology, Journal Year: 2023, Volume and Issue: 231, P. 102534 - 102534

Published: Sept. 30, 2023

Language: Английский

---

The β‐adrenergic hypothesis of synaptic and microglial impairment in Alzheimer's disease

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 165(3), P. 289 - 302

Published: Feb. 17, 2023

Alzheimer's disease (AD) is a progressive neurodegenerative originating partly from amyloid β protein-induced synaptic failure. As damaging of noradrenergic neurons in the locus coeruleus (LC) occurs at prodromal stage AD, activation adrenergic receptors could serve as first line defense against onset disease. Activation β2 -ARs strengthens long-term potentiation (LTP) and activity, thus improving learning memory. Physical stimulation animals exposed to an enriched environment (EE) leads prevents dysfunction. EE also suppresses neuroinflammation, suggesting that -AR agonists may play neuroprotective role. The used for respiratory diseases have been shown anti-inflammatory effect. Epidemiological studies further support beneficial effects on several diseases. Thus, I propose provide therapeutic value combination with novel treatments AD.

Language: Английский

---

Amyloid Β Fragments that Suppress Oligomers But Not Fibrils are Cytoprotective

Published: Jan. 1, 2025

Language: Английский

---

Beneficial effect of extract powder of Juncus effusus enriched with dehydroeffusol on cognitive and dexterous performance of elderly people −A randomized, double-blind, placebo-controlled, parallel-group study−

Nutrition, Journal Year: 2025, Volume and Issue: 134, P. 112712 - 112712

Published: Feb. 8, 2025

Language: Английский

---

Amyloid β fragments that suppress oligomers but not fibrils are cytoprotective

Archives of Biochemistry and Biophysics, Journal Year: 2025, Volume and Issue: unknown, P. 110386 - 110386

Published: March 1, 2025

Language: Английский

---