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

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Авг. 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.

Язык: Английский

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Links between COVID-19 and Parkinson’s disease/Alzheimer’s disease: reciprocal impacts, medical care strategies and underlying mechanisms

Translational Neurodegeneration, Год журнала: 2023, Номер 12(1)

Опубликована: Янв. 30, 2023

Abstract The impact of coronavirus disease 2019 (COVID-19) pandemic on patients with neurodegenerative diseases and the specific neurological manifestations COVID-19 have aroused great interest. However, there are still many issues concern to be clarified. Therefore, we review current literature complex relationship between an emphasis Parkinson’s (PD) Alzheimer’s (AD). We summarize infection symptom severity, progression, mortality rate PD AD, discuss whether could trigger AD. In addition, susceptibility prognosis in AD also included. order achieve better management patients, modifications care strategies, drug therapies, vaccines during listed. At last, mechanisms underlying link reviewed.

Язык: Английский

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ApoE4 associated with severe COVID-19 outcomes via downregulation of ACE2 and imbalanced RAS pathway

Journal of Translational Medicine, Год журнала: 2023, Номер 21(1)

Опубликована: Фев. 9, 2023

Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk severity of coronavirus disease 2019 (COVID-19), yielded inconsistent results. Severe acute respiratory syndrome 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme (ACE2) receptor expressed host cell membranes.A meta-analysis was conducted clarify between COVID-19. Multiple interaction assays were utilized investigate potential molecular link SARS-CoV-2 primary ACE2, protein. Immunoblotting immunofluorescence staining methods used access regulatory effect different isoform ACE2 expression.ApoE gene (ε4 carrier genotypes VS non-ε4 genotypes) is increased (P = 0.0003, OR 1.44, 95% CI 1.18-1.76) progression < 0.00001, 1.85, 1.50-2.28) interacts both but did not show isoform-dependent effects. ApoE4 significantly downregulates expression in vitro vivo subsequently decreases conversion Ang II 1-7.ApoE4 increases infectivity a manner may depend differential interactions or ACE2. Instead, dysregulation renin-angiotensin system (RAS) provide explanation by which exacerbates COVID-19 disease.

Язык: Английский

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Apolipoprotein E and viral infection: Risks and Mechanisms

Molecular Therapy — Nucleic Acids, Год журнала: 2023, Номер 33, С. 529 - 542

Опубликована: Июль 29, 2023

Apolipoprotein E (ApoE) is a multifunctional protein critical for lipid metabolism and cholesterol homeostasis. In addition to being well known genetic determinant of both neurodegenerative cardiovascular diseases, ApoE frequently involved in various viral infection-related diseases. Human functionally polymorphic with three isoforms, namely, ApoE2, ApoE3, ApoE4, markedly altered structures functions. ApoE4 associated increased susceptibility infection herpes simplex virus type-1 HIV. Conversely, protects against hepatitis C B infection. With the outbreak coronavirus disease 2019, has been shown determine incidence progression severe acute respiratory syndrome 2 These findings clearly indicate role Furthermore, polymorphism or even opposite effects these processes, which are partly related structural features that distinguish different statuses. current review, we summarize emerging relationship between infection, discuss potential mechanisms, identify future directions may help advance our understanding link

Язык: Английский

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Deep spatial proteomics reveals region-specific features of severe COVID-19-related pulmonary injury

Cell Reports, Год журнала: 2024, Номер 43(2), С. 113689 - 113689

Опубликована: Янв. 21, 2024

As a primary target of severe acute respiratory syndrome coronavirus 2, lung exhibits heterogeneous histopathological changes following infection. However, comprehensive insight into their protein basis with spatial resolution remains deficient, which hinders further understanding disease 2019 (COVID-19)-related pulmonary injury. Here, we generate region-resolved proteomic atlas hallmark pathological structures by integrating histological examination, laser microdissection, and ultrasensitive proteomics. Over 10,000 proteins are quantified across 71 post-mortem specimens. We identify spectrum pathway dysregulations in alveolar epithelium, bronchial blood vessels compared non-COVID-19 controls, providing evidence for transitional-state pneumocyte hyperplasia. Additionally, our data reveal the region-specific enrichment functional markers bronchiole mucus plugs, fibrosis, airspace inflammation, type 2 cells, uncovering distinctive features. Furthermore, detect increased expression associated viral entry inflammatory response multiple regions, suggesting potential therapeutic targets. Collectively, this study provides distinct perspective deciphering COVID-19-caused dysfunction

Язык: Английский

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Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Май 31, 2023

Abstract Background Mutations in colony-stimulating factor 1 receptor (CSF1R) are known to cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), which has been recently demonstrated as a primary microgliopathy characterized by cognitive impairment. Although the molecular mechanism underlying CSF1R-mediated remains unclear, therapeutic strategies have generally targeted modulation of microglial function. In particular, inhibitor, minocycline, shown attenuate learning memory deficits several neurodegenerative diseases. The objectives this study were investigate pathogenic mechanisms ALSP explore effects minocycline an vivo model ALSP. We hypothesized that inhibiting activation via could reverse behavior pathological defects mice. Methods generated Csf1r haploinsufficiency mouse using CRISPR/Cas9 genome editing conducted electrophysiological recordings long-term potentiation (LTP) behavioral tests validate recapitulation clinical characteristics 8- 11-month-old RNA-sequencing was used enriched gene expression pathogenesis Microglial assessed immunofluorescent detection Iba1 CD68 brain sections male mice pro-inflammatory phagocytosis +/− microglia. Therapeutic tests, histological analysis, morphological examination after four weeks intraperitoneal injection or vehicle control wild-type littermates. Results found synaptic function reduced LTP neurons hippocampal CA1 region, while showed impaired spatial specifically Increased activation, cytokine production, enhanced phagocytic capacity also observed Treatment suppress microglia both vitro vivo. Notably, partially rescued administration, potentially due inhibition inflammation Conclusions Our shows CSF1R deficiency results aberrant phenotype myelin. indicate can ameliorate impairment CSF1R-deficient mice, suggesting potential target for CSF1R-related leukoencephalopathy. Collectively, these data support confers protective against

Язык: Английский

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Amyloid precursor protein facilitates SARS-CoV-2 virus entry into cells and enhances amyloid-β-associated pathology in APP/PS1 mouse model of Alzheimer’s disease

Translational Psychiatry, Год журнала: 2023, Номер 13(1)

Опубликована: Дек. 16, 2023

Although there are indications of a trend towards less severe acute respiratory symptoms and decline in overall lethality from the novel Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome 2 (SARS-CoV-2), more attention has been paid to long COVID, including increased risk Alzheimer's disease (AD) COVID-19 patients. In this study, we aim investigate involvement N-terminal amyloid precursor protein (APP) SARS-CoV-2-induced amyloid-β (Aβ) pathology. Utilizing both vitro vivo methodologies, first investigated interaction between spike SARS-CoV-2 APP via LSPR CoIP assays. The impacts overexpression on virus infection were further evaluated HEK293T/ACE2 cells, SH-SY5Y Vero cells. We also analyzed pseudovirus mouse model overexpressing human wild-type APP. Finally, impact within brain organoids assessed chronic effects Aβ levels. reported here for time that APP, AD, interacts with Spike SARS-CoV-2. Moreover, data indicated promotes cellular entry virus, exacerbates Aβ-associated pathology APP/PS1 which can be ameliorated blockage. Our findings provide experimental evidence interpret APP-related mechanisms underlying AD-like neuropathology patients may pave way help inform management therapeutic strategies against diseases accordingly.

Язык: Английский

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Pathogenic mechanisms of cardiovascular damage in COVID-19

Molecular Medicine, Год журнала: 2024, Номер 30(1)

Опубликована: Июнь 19, 2024

Abstract Background COVID-19 is a new infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2). Since outbreak in December 2019, it has an unprecedented world pandemic, leading to global human health crisis. Although SARS CoV-2 mainly affects lungs, causing interstitial pneumonia and distress syndrome, number of patients often have extensive clinical manifestations, such as gastrointestinal symptoms, cardiovascular damage renal dysfunction. Purpose This review article discusses pathogenic mechanisms provides some useful suggestions for future diagnosis, treatment prevention. Methods An English-language literature search was conducted PubMed Web Science databases up 12th April, 2024 terms “COVID-19”, “SARS CoV-2”, “cardiovascular damage”, “myocardial injury”, “myocarditis”, “hypertension”, “arrhythmia”, “heart failure” “coronary heart disease”, especially update articles 2023 2024. Salient medical literatures regarding were selected, extracted synthesized. Results The most common myocarditis pericarditis, hypertension, arrhythmia, myocardial injury failure, coronary disease, stress cardiomyopathy, ischemic stroke, blood coagulation abnormalities, dyslipidemia. Two important may be direct viral cytotoxicity well indirect hyperimmune responses body infection. Conclusions Cardiovascular portends worse prognosis. underlying pathophysiological related are not completely clear, two SARSCoV-2 infection responses.

Язык: Английский

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Identification of biomarkers in Alzheimer’s disease and COVID-19 by bioinformatics combining single-cell data analysis and machine learning algorithms

PLoS ONE, Год журнала: 2025, Номер 20(2), С. e0317915 - e0317915

Опубликована: Фев. 18, 2025

Background Since its emergence in 2019, COVID-19 has become a global epidemic. Several studies have suggested link between Alzheimer’s disease (AD) and COVID-19. However, there is little research into the mechanisms underlying these phenomena. Therefore, we conducted this study to identify key genes associated with AD, evaluate their correlation immune cells characteristics metabolic pathways. Methods Transcriptome analyses were used common biomolecular markers of AD Differential expression analysis weighted gene co-expression network (WGCNA) performed on chip datasets (GSE213313, GSE5281, GSE63060) from patients both conditions. Gene ontology (GO) enrichment identified molecular mechanisms. The core using machine learning. Subsequently, evaluated relationship Finally, our findings validated through single-cell analysis. Results 484 differentially expressed (DEGs) by taking intersection black module, containing 132 genes, showed highest association two diseases according WGCNA. GO revealed that mainly affect inflammation, cytokines, immune-related functions, signaling pathways related metal ions. Additionally, learning approach eight genes. We links also found EIF3H oxidative phosphorylation. Conclusion This identifies shared pathways, alterations, changes potentially contributing pathogenesis AD.

Язык: Английский

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Long-term outcomes of patients with a pre-existing neurological condition after SARS-CoV-2 infection

Journal of the Neurological Sciences, Год журнала: 2025, Номер unknown, С. 123477 - 123477

Опубликована: Апрель 1, 2025

Язык: Английский

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