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

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Engineered Extracellular Vesicles with SHP2 High Expression Promote Mitophagy for Alzheimer's Disease Treatment

Advanced Materials, Journal Year: 2022, Volume and Issue: 34(49)

Published: Oct. 4, 2022

Mitochondrial dysfunction is a fundamental pathological feature of Alzheimer's disease (AD). However, toxicity and poor brain enrichment existing mitophagy inducers limit their further applications. In this study, platform for AD therapy developed using nanosized mesenchymal-stem-cells-derived extracellular vesicles with tyrosine phosphatase-2 (SHP2) high-expression (MSC-EVs-SHP2). The high blood-brain barrier penetration ability MSC-EVs-SHP2 demonstrated in AD-mice, facilitating SHP2 delivery to the brain. addition, significantly induces neuronal cells, which alleviates mitochondrial damage-mediated apoptosis NLRP3 inflammasome activation. Mitophagy diminishes cells neuroinflammation, culminating rescued synaptic loss cognitive decline an mouse model. EV-engineering technology provides potential effective by inducing mitophagy.

Language: Английский

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Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

Cells, Journal Year: 2022, Volume and Issue: 11(8), P. 1367 - 1367

Published: April 17, 2022

Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel complex interconnected pathophysiology of AD, clinical trial failure rates high, no disease-modifying therapies are presently available. Fluid biomarker discovery for AD rapidly expanding field research aimed at anticipating diagnosis following progression over time. Currently, Aβ

Language: Английский

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The dynamics of plasma biomarkers across the Alzheimer’s continuum

Alzheimer s Research & Therapy, Journal Year: 2023, Volume and Issue: 15(1)

Published: Feb. 8, 2023

Failures in drug trials strengthen the necessity to further determine neuropathological events during development of Alzheimer's disease (AD). We sought investigate dynamic changes and performance plasma biomarkers across entire continuum Chinese population.Plasma amyloid-β (Αβ)42, Aβ40, Aβ42/Aβ40, phosphorylated tau (p-tau)181, neurofilament light (NfL), glial fibrillary acidic protein (GFAP) were measured utilizing ultrasensitive single-molecule array technology AD (n=206), wherein Aβ status was defined by values cerebrospinal fluid (CSF) Aβ42 or positron emission tomography (PET). Their trajectories compared with those putative CSF biomarkers.Plasma GFAP p-tau181 increased only Aβ-positive individuals throughout aging, whereas NfL aging regardless status. Among studied, one that changed first. It had a prominent elevation early cognitively unimpaired (CU) A+T- phase (CU phase: 97.10±41.29 pg/ml; CU A-T- 49.18±14.39 p<0.001). From preclinical symptomatic stages AD, started rise sharply as soon became abnormal continued increase until reaching its highest level dementia phase. The greatest slope change seen GFAP. This is followed total-tau, and, lesser extent, then p-tau181. In contrast, NfL, Aβ42, Aβ40 less pronounced. Of note, these exhibited smaller ranges than their counterparts, except for which opposite. Plasma tightly associated pathologies amyloid tracer uptake widespread brain areas. could accurately identify (area under curve (AUC)=0.911) PET (AUC=0.971) positivity. also performed well discriminating (AUC=0.916), discriminative accuracy relatively low other biomarkers.This study first delineate population, providing important implications future targeting facilitate prevention treatment.

Language: Английский

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Salivary Biomarkers for Alzheimer’s Disease: A Systematic Review with Meta-Analysis

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1168 - 1168

Published: Jan. 18, 2024

Alzheimer’s Disease (AD) is the most common neurodegenerative disease which manifests with progressive cognitive impairment, leading to dementia. Considering noninvasive collection of saliva, we designed systematic review answer question “Are salivary biomarkers reliable for diagnosis Disease?” Following inclusion and exclusion criteria, 30 studies were included in this (according PRISMA statement guidelines). Potential include mainly proteins, metabolites even miRNAs. Based on meta-analysis, AD patients, levels beta-amyloid42 p-tau significantly increased, t-tau lactoferrin decreased at borderline statistical significance. However, according pooled AUC, showed a significant predictive value salivary-based diagnosis. In conclusion, potential markers such as beta-amyloid42, tau can be detected saliva could reliably support early disease.

Language: Английский

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Detecting Early Cognitive Decline in Alzheimer’s Disease with Brain Synaptic Structural and Functional Evaluation

Biomedicines, Journal Year: 2023, Volume and Issue: 11(2), P. 355 - 355

Published: Jan. 26, 2023

Early cognitive decline in patients with Alzheimer's (AD) is associated quantifiable structural and functional connectivity changes the brain. AD dysregulation of Aβ tau metabolism progressively disrupt normal synaptic function, leading to loss synapses, decreased hippocampal density early atrophy. Advances brain imaging techniques living have enabled transition from clinical signs symptoms-based diagnosis biomarkers-based diagnosis, techniques, quantitative EEG, body fluids sampling. The hippocampus has a central role semantic episodic memory processing. This function critically dependent on intrahippocampal connections many cortical regions, including perirhinal entorhinal cortex, parahippocampal association regions temporal parietal lobes, prefrontal cortex. Therefore, reflected altered intrinsic networks (aka large-scale networks), memory, default mode, salience networks. narrative review discusses recent critical issues related detecting AD-associated markers high-risk or neuropsychologically diagnosed subjective impairment mild impairment.

Language: Английский

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Neuronal ApoE4 in Alzheimer’s disease and potential therapeutic targets

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: June 2, 2023

The most prevalent genetic risk factor for Alzheimer’s disease (AD) is Apolipoprotein E (ApoE), a gene located on chromosome 19 that encodes three alleles (e2, e3, and e4) give rise to the ApoE subtypes E2, E3, E4, respectively. E2 E4 have been linked increased plasma triglyceride concentrations are known play critical role in lipoprotein metabolism. prominent pathological features of AD mainly include senile plaques formed by amyloid β (Aβ 42 ) aggregation neuronal fibrous tangles (NFTs), deposited composed Aβ hyperphosphorylation truncated head. In central nervous system, protein primarily derived from astrocytes, but also produced when neurons stressed or affected certain stress, injury, aging conditions. ApoE4 induces tau pathologies, leading neuroinflammation damage, impairing learning memory functions. However, how mediates pathology remains unclear. Recent studies shown may lead greater neurotoxicity, which increases development. This review focuses pathophysiology explains deposition, mechanisms hyperphosphorylation, potential therapeutic targets.

Language: Английский

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Molecular mechanisms of phase separation and amyloidosis of ALS/FTD-linked FUS and TDP-43

Aging and Disease, Journal Year: 2023, Volume and Issue: 15(5), P. 2084 - 2084

Published: Nov. 18, 2023

FUS and TDP-43, two RNA-binding proteins from the heterogeneous nuclear ribonucleoprotein family, have gained significant attention in field of neurodegenerative diseases due to their association with amyotrophic lateral sclerosis (ALS) frontotemporal degeneration (FTD). They possess folded domains for binding ATP various nucleic acids including DNA RNA, as well substantial intrinsically disordered regions (IDRs) prion-like (PLDs) RG-/RGG-rich regions. play vital roles cellular processes, transcription, splicing, microRNA maturation, RNA stability transport repair. In particular, they are key components forming granules stress (SGs) through homotypic or heterotypic liquid-liquid phase separation (LLPS). Strikingly, liquid-like droplets formed by TDP-43 may undergo aging transform into less dynamic assemblies such hydrogels, inclusions, amyloid fibrils, which pathological hallmarks ALS FTD. This review aims synthesize consolidate biophysical knowledge sequences, structures, stability, dynamics, inter-domain interactions domains, so shed light on molecular mechanisms underlying (LLPS) amyloidosis. The further delves ALS-causing mutants well-folded hPFN1 disrupt dynamics LLPS domain, providing insights a potential mechanism misfolding/aggregation-prone cause gain functions. With better understanding different aspects ultimate goal is develop drugs targeting amyloidosis, could mediate protein homeostasis within cells lead new treatments currently intractable diseases, particularly ALS, FTD aging. However, study membrane-less organelles condensates still its infancy therefore also highlights questions that require future investigation.

Language: Английский

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Updates in Alzheimer's disease: from basic research to diagnosis and therapies

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Sept. 4, 2024

Language: Английский

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A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology

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

Published: April 28, 2024

Abstract Impaired brain glucose metabolism is an early indicator of Alzheimer’s disease (AD); however, the fundamental mechanism unknown. In this study, we found a substantial decline in isocitrate dehydrogenase 3β (IDH3β) levels, critical tricarboxylic acid cycle enzyme, AD patients and AD-transgenic mice’s brains. Further investigations demonstrated that knockdown IDH3β induced oxidation-phosphorylation uncoupling, leading to reduced energy lactate accumulation. The resulting increased lactate, source lactyl, was promote histone lactylation, thereby enhancing expression paired-box gene 6 (PAX6). As inhibitory transcription factor IDH3β, elevated PAX6 turn inhibited tau hyperphosphorylation, synapse impairment, learning memory deficits resembling those seen AD. mice, upregulating downregulating were improve cognitive functioning reverse AD-like pathologies. Collectively, our data suggest impaired oxidative phosphorylation accelerates progression via positive feedback inhibition loop IDH3β-lactate-PAX6-IDH3β. Breaking by or attenuates neurodegeneration impairments.

Language: Английский

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