Molecular Neurobiology, Journal Year: 2024, Volume and Issue: 61(8), P. 5494 - 5509
Published: Jan. 10, 2024
Language: Английский
Translational Neurodegeneration, Journal Year: 2022, Volume and Issue: 11(1)
Published: March 18, 2022
Alzheimer's disease (AD) is the most common neurodegenerative in elderly worldwide. However, complexity of AD pathogenesis leads to discrepancies understanding this disease, and may be main reason for failure drug development. Fortunately, many ongoing preclinical clinical studies will continually open up avenues unravel mechanisms guide strategies diagnosis For example, immunotherapeutic targeting amyloid-β (Aβ) tau proteins were once deemed almost certainly effective treatment due excellent results. repeated failures trials on vaccines humanized anti-Aβ anti-tau monoclonal antibodies have resulted doubts strategy. Recently, a new antibody (Aducanumab) has been approved by US Food Drug Administration, which brings us back realization that immunotherapy Aβ still promising. Meanwhile, immunotherapies based other targets such as tau, microglia gut-brain axis are also under Further research needed clarify forms epitopes targeted improve accuracy effectiveness drugs. In review, we focus Aβ, their action AD. addition, present up-to-date advances future perspectives
Language: Английский
Citations
166
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
Citations
135
Journal of Neuroscience, Journal Year: 2022, Volume and Issue: 42(27), P. 5294 - 5313
Published: June 7, 2022
The mechanistic target of rapamycin (mTOR) signaling pathway plays a major role in key cellular processes including metabolism and differentiation; however, the mTOR microglia its importance Alzheimer9s disease (AD) have remained largely uncharacterized. We report that selective loss Tsc1, negative regulator mTOR, mice both sexes, caused activation upregulation Trem2 with enhanced β-Amyloid (Aβ) clearance, reduced spine loss, improved cognitive function 5XFAD AD mouse model. Combined Tsc1 Trem2 led to Aβ clearance increased plaque burden revealing functions downstream mTOR. mutant showed phagocytosis CD68 Lamp1 lysosomal proteins. In vitro studies using Tsc1-deficient revealed endocytosis tracker indicator Green DND-26 suggesting activity. Incubation fluorescent-labeled uptake which was blunted by rapamycin, an inhibitor. vivo treatment relevant genotypes background affected microglial activity, decreased expression causing increase burden. Prolonged even further reduction expression, levels. Together, our findings reveal is critically linked regulation biogenesis, through could be exploited toward better therapeutic avenues Aβ-related pathologies. SIGNIFICANCE STATEMENT Mechanistic for metabolic processes. However, link between not well understood. In this study, we provide compelling in evidence would benefit (Aβ)-related pathologies, as it upregulates Trem2, receptor uptake. Inhibition well-established immunosuppressant, downregulated indicating inactivation may detrimental Aβ-associated patients. This finding will significant public health impact benefit, regarding usage patients, believe aggravate
Language: Английский
Citations
75
The Lancet Healthy Longevity, Journal Year: 2023, Volume and Issue: 4(3), P. e115 - e125
Published: March 1, 2023
Language: Английский
Citations
46
Angiogenesis, Journal Year: 2023, Volume and Issue: 27(1), P. 5 - 22
Published: April 27, 2023
Language: Английский
Citations
45
Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15
Published: May 24, 2024
Alois Alzheimer described the first patient with Alzheimer’s disease (AD) in 1907 and today AD is most frequently diagnosed of dementias. a multi-factorial neurodegenerative disorder familial, life style comorbidity influences impacting global population more than 47 million projected escalation by 2050 to exceed 130 million. In USA demographic encompasses approximately six individuals, expected increase surpass 13 2050, antecedent phase AD, recognized as mild cognitive impairment (MCI), involves nearly 12 individuals. The economic outlay for management AD-related decline estimated at 355 billion USD. addition, intensifying prevalence cases countries modest intermediate income further enhances urgency therapeutically cost-effective treatments improving quality patients their families. This narrative review evaluates pathophysiological basis an initial focus on therapeutic efficacy limitations existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, N-methyl-D-aspartate receptor (NMDA) allosteric modulator, memantine. hypothesis amyloid-β (Aβ) tau are appropriate targets have potential halt progress critically analyzed particular clinical trial data anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab donanemab. challenges dogma targeting Aβ will benefit majority subjects MABs unlikely be “magic bullet”. A comparison benefits disadvantages different classes forms determining new directions research alternative drug undergoing pre-clinical assessments. we discuss stress importance treatment co-morbidities, including hypertension, diabetes, obesity depression known risk developing AD.
Language: Английский
Citations
21
Journal of Neural Transmission, Journal Year: 2021, Volume and Issue: 129(1), P. 1 - 24
Published: Dec. 17, 2021
Language: Английский
Citations
86
International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 13630 - 13630
Published: Nov. 7, 2022
Alzheimer’s disease (AD) is a frequent and disabling neurodegenerative disorder, in which astrocytes participate several pathophysiological processes including neuroinflammation, excitotoxicity, oxidative stress lipid metabolism (along with critical role apolipoprotein E function). Current evidence shows that have both neuroprotective neurotoxic effects depending on the stage microenvironmental factors. Furthermore, appear to be affected by presence of amyloid-beta (Aβ), alterations calcium levels, gliotransmission proinflammatory activity via RAGE-NF-κB pathway. In addition, play an important tau clearance Aβ through glymphatic system. this review, we will discuss novel pharmacological non-pharmacological treatments focused as therapeutic targets for AD. These interventions include anti-inflammatory/antioxidant systems, glutamate activity, metabolism, neurovascular coupling system, dysregulation, release peptides affects glial neuronal function. According AD stage, these therapies may benefit either preventing or delaying progression disease.
Language: Английский
Citations
64
Antioxidants, Journal Year: 2023, Volume and Issue: 12(7), P. 1460 - 1460
Published: July 20, 2023
Alzheimer’s disease (AD) is the most common cause of dementia, characterised by a marked decline both memory and cognition, along with pathophysiological hallmarks including amyloid beta peptide (Aβ) accumulation, tau protein hyperphosphorylation, neuronal loss inflammation in brain. Additionally, oxidative stress caused an imbalance between free radicals antioxidants considered one main risk factors for AD, since it can result protein, lipid nucleic acid damage exacerbate Aβ pathology. To date, there lack successful pharmacological approaches to cure or even ameliorate terrible impact this disease. Due this, dietary compounds antioxidative anti-inflammatory properties acquire special relevance as potential therapeutic agents. In context, green tea, its bioactive compound, epigallocatechin-3-gallate (EGCG), have been targeted plausible option modulation AD. Specifically, EGCG acts antioxidant regulating inflammatory processes involved neurodegeneration such ferroptosis microglia-induced cytotoxicity inducing signalling pathways related survival. Furthermore, reduces hyperphosphorylation aggregation promotes non-amyloidogenic route APP processing, thus preventing formation subsequent accumulation. Taken together, these results suggest that may be suitable candidate search neurodegenerative disorders involving stress,
Language: Английский
Citations
32
International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(15), P. 12464 - 12464
Published: Aug. 5, 2023
While a certain level of inflammation is critical for humans to survive infection and injury, prolonged inflammatory response can have fatal consequences. Pattern recognition Toll-like receptors (TLRs) are key players in the initiation an process. TLR2 one most studied pattern (PRRs) known form heterodimers with either TLR1, TLR4, TLR6, TLR10, allowing it recognize wide range pathogens. Although large number studies been conducted over past decades, there still many unanswered questions regarding mechanisms health disease. In this review, we provide up-to-date overview TLR2, including its homo- heterodimers. Furthermore, will discuss pro- anti-inflammatory properties recent findings prominent TLR2-associated infectious neurodegenerative diseases.
Language: Английский
Citations
24