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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Alzheimer’s Disease Seen through the Eye: Ocular Alterations and Neurodegeneration

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(5), P. 2486 - 2486

Published: Feb. 24, 2022

Alzheimer's Disease (AD) is one of the main neurodegenerative diseases worldwide. Unfortunately, AD shares many similarities with other dementias at early stages, which impedes an accurate premortem diagnosis. Therefore, it urgent to find biomarkers allow for diagnosis disease. There increasing scientific evidence highlighting between eye and structures CNS, suggesting that knowledge acquired in research could be useful AD. For example, retina optic nerve are considered part central nervous system, their damage can result retrograde anterograde axon degeneration, as well abnormal protein aggregation. In anterior segment, aqueous humor tear film may comparable cerebrospinal fluid. Both fluids enriched molecules potential biomarkers. Indeed, pathophysiology AD, characterized by cerebral deposits amyloid-beta (Aβ) tau protein, also present eyes patients, besides numerous structural functional changes observed structure eyes. all this suggests ocular have used either predictive values assessment or diagnostic tools.

Language: Английский

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Reconsidering the role of blood-brain barrier in Alzheimer’s disease: From delivery to target

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

Published: Feb. 16, 2023

The existence of a selective blood-brain barrier (BBB) and neurovascular coupling are two unique central nervous system vasculature features that result in an intimate relationship between neurons, glia, blood vessels. This leads to significant pathophysiological overlap neurodegenerative cerebrovascular diseases. Alzheimer's disease (AD) is the most prevalent whose pathogenesis still be unveiled but has mostly been explored under light amyloid-cascade hypothesis. Either as trigger, bystander, or consequence neurodegeneration, vascular dysfunction early component pathological conundrum AD. anatomical functional substrate this degeneration BBB, dynamic semi-permeable interface consistently shown defective. Several molecular genetic changes have demonstrated mediate BBB disruption isoform ε4 Apolipoprotein E at same time strongest risk factor for AD known promoter dysfunction. Low-density lipoprotein receptor-related protein 1 (LRP-1), P-glycoprotein, receptor advanced glycation end products (RAGE) examples transporters implicated its due their role trafficking amyloid-β. currently devoid strategies change natural course burdening illness. unsuccess may partly explained by our misunderstanding inability develop drugs effectively delivered brain. represent therapeutic opportunity target itself vehicle. In review, we aim explore including background detail how it can targeted future research.

Language: Английский

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Biomarkers Assessing Endothelial Dysfunction in Alzheimer’s Disease

Cells, Journal Year: 2023, Volume and Issue: 12(6), P. 962 - 962

Published: March 22, 2023

Alzheimer's disease (AD) is the most common degenerative disorder in elderly developed countries. Currently, growing evidence pointing at endothelial dysfunction as a key player cognitive decline course of AD. As main component blood-brain barrier (BBB), cells driven by vascular risk factors associated with AD allows passage toxic substances to cerebral parenchyma, producing chronic hypoperfusion that eventually causes an inflammatory and neurotoxic response. In this process, levels several biomarkers are disrupted, such increase adhesion molecules allow leukocytes increasing permeability BBB; moreover, other players, including endothelin-1, also mediate artery inflammation. consequence disruption BBB, progressive neuroinflammatory response produced that, added astrogliosis, triggers neuronal degeneration (possibly responsible for deterioration). Recently, new have been proposed early can constitute therapeutic targets well diagnostic prognostic markers

Language: Английский

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Alzheimer's disease pathology: pathways between chronic vascular risk factors and blood-brain barrier dysfunction in a cohort of patients with different types of dementia

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

Published: May 4, 2023

Blood brain barrier (BBB) breakdown is considered a potential mechanism of dementia. The Alzheimer's disease (AD) biomarkers and vascular factors are also associated with BBB permeability.In the present study, combination effects neuropathological AD chronic risk for were investigated.The cerebrospinal fluid (CSF)/serum albumin ratio (Qalb), an indicator permeability, was measured in total 95 hospitalized dementia patients. demographics, clinical information, laboratory tests collected from inpatient records. CSF apolipoprotein E (APOE) genotype collected. mediation analysis model used to calculate associations among (mediator), Qalb, factors.Three types dementia, (n = 52), Lewy body (LBD, n 19), frontotemporal lobar degeneration 24), included mean Qalb 7.18 (± 4.36). significantly higher patients type 2 diabetes mellitus (T2DM, p 0.004) but did not differ based on presence APOE ε4 allele, CMBs, or amyloid/tau/neurodegeneration (ATN) framework. negatively levels Aβ1-42 (B -20.775, 0.009) Aβ1-40 -305.417, 0.005) positively T2DM 3.382, < 0.001) glycosylated hemoglobin (GHb, B 1.163, fasting blood glucose (FBG, 1.443, 0.001). GHb direct factor (total effect 1.135, 95% CI: 0.611-1.659, Ratios Aβ1-42/Aβ1-40 t-tau/Aβ1-42 mediators association between GHb; 1.178 (95% 0.662-1.694, 0.001).Glucose exposure can directly indirectly affect integrity through Aβ tau, indicating affects stability plays important role protection management.

Language: Английский

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Association Between Body Composition Patterns, Cardiovascular Disease, and Risk of Neurodegenerative Disease in the UK Biobank

Neurology, Journal Year: 2024, Volume and Issue: 103(4)

Published: July 24, 2024

Accumulating evidence connects diverse components of body composition (e.g., fat, muscle, and bone) to neurodegenerative disease risk, yet their interplay remains underexplored. This study examines the associations between patterns risk diseases, exploring mediating role cardiovascular diseases (CVDs).

Language: Английский

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Predictive network analysis identifies JMJD6 and other potential key drivers in Alzheimer’s disease

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: May 15, 2023

Abstract Despite decades of genetic studies on late-onset Alzheimer’s disease, the underlying molecular mechanisms remain unclear. To better comprehend its complex etiology, we use an integrative approach to build robust predictive (causal) network models using two large human multi-omics datasets. We delineate bulk-tissue gene expression into single cell-type and integrate clinical pathologic traits, nucleotide variation, deconvoluted for construction cell type-specific models. Here, focus neuron-specific prioritize 19 predicted key drivers modulating pathology, which then validate by knockdown in induced pluripotent stem cell-derived neurons. find that neuronal 10 targets significantly modulates levels amyloid-beta and/or phosphorylated tau peptides, most notably JMJD6 . also confirm our structure RNA sequencing neurons following each targets, additionally predicts they are upstream regulators REST VGF. Our work thus identifies Alzheimer’s-associated state may represent therapeutic with relevance both amyloid pathology disease.

Language: Английский

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Endothelial Senescence and Its Impact on Angiogenesis in Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(14), P. 11344 - 11344

Published: July 12, 2023

Endothelial cells are constantly exposed to environmental stress factors that, above a certain threshold, trigger cellular senescence and apoptosis. The altered vascular function affects new vessel formation endothelial fitness, contributing the progression of age-related diseases. This narrative review highlights complex interplay between senescence, oxidative stress, extracellular vesicles, matrix emphasizes crucial role angiogenesis in aging Alzheimer's disease. interaction nervous systems is essential for development healthy brain, especially since neurons exceptionally dependent on nutrients carried by blood. Therefore, anomalies delicate balance pro- antiangiogenic consequences disrupted angiogenesis, such as misalignment, leakage disturbed blood flow, responsible neurodegeneration. implications non-productive disease due dysregulated Delta-Notch VEGF signaling further explored. Additionally, potential therapeutic strategies exercise caloric restriction modulate mitigate associated debilitating symptoms discussed. Moreover, both roles vesicles stress-induced an early detection marker considered. intricate relationship provides valuable insights into mechanisms underlying angiogenesis-related disorders opens avenues future research interventions.

Language: Английский

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Improvements in Exercise for Alzheimer’s Disease: Highlighting FGF21-Induced Cerebrovascular Protection

Neurochemical Research, Journal Year: 2025, Volume and Issue: 50(2)

Published: Feb. 4, 2025

Language: Английский

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Endothelial Progenitor Cells and Cerebral Small Vessel Disease in APOE4 Carriers

Cerebral Circulation - Cognition and Behavior, Journal Year: 2025, Volume and Issue: 8, P. 100378 - 100378

Published: Jan. 1, 2025

APOE4 carriers at genetic risk for Alzheimer's disease exhibit early cerebrovascular dysfunction, which may be triggered by endothelial dysfunction. Endothelial progenitor cells (EPCs) represent cell populations involved in promoting angiogenesis and facilitating vascular repair response to injury. We examined whether elevated EPCs are associated with lower cerebral small vessel burden prior cognitive decline. Independently living older adults (N = 109, mean age 70.5 years; SD 7.9; 34.9 % male) free of dementia or clinical stroke underwent brain MRI venipuncture. Small was determined using a validated scale. White matter hyperintensity (WMH) volume the lesion segmentation toolbox. PBMCs were cultured defined as number colony forming units vitro. Regression analysis revealed an association between average EPC colonies load (p .026) WMH .002), carriers. Findings suggest that count indicate activation mechanisms protect function development

Language: Английский

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