Frontotemporal dementia. How to deal with its diagnostic complexity? DOI Creative Commons
Annibale Antonioni,

Emanuela Maria Raho,

Enrico Granieri

et al.

Expert Review of Neurotherapeutics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Frontotemporal dementia (FTD) encompasses a group of heterogeneous neurodegenerative disorders. Aside from genetic cases, its diagnosis is challenging, particularly in the early stages when symptoms are ambiguous, and structural neuroimaging does not reveal characteristic patterns. The authors performed comprehensive literature search through MEDLINE, Scopus, Web Science databases to gather evidence aid diagnostic process for suspected FTD patients, phases, even sporadic ranging established promising tools. Blood-based biomarkers might help identify very neuropathological guide further evaluations. Subsequently, neurophysiological measures reflecting functional changes cortical excitatory/inhibitory circuits, along with assessing brain network, connectivity, metabolism, perfusion alterations, could detect specific associated decades before symptom onset. As advances, cognitive-behavioral profiles atrophy patterns emerge, distinguishing subtypes. Emerging disease-modifying therapies require patient enrollment. Therefore, paradigm shift needed - relying on typical cognitive advanced cases widely applicable biomarkers, primarily fluid and, subsequently, where appropriate. Additionally, exploring subjective complaints behavioral detected by home-based technologies be crucial diagnosis.

Language: Английский

Nanoparticle-Based Drug Delivery Systems: An Inspiring Therapeutic Strategy for Neurodegenerative Diseases DOI Open Access

Linyan Duan,

Xingfan Li,

Rong Ji

et al.

Polymers, Journal Year: 2023, Volume and Issue: 15(9), P. 2196 - 2196

Published: May 5, 2023

Neurodegenerative diseases are common, incurable neurological disorders with high prevalence, and lead to memory, movement, language, intelligence impairments, threatening the lives health of patients worldwide. The blood–brain barrier (BBB), a physiological between central nervous system peripheral blood circulation, plays an important role in maintaining homeostasis intracerebral environment by strictly regulating transport substances brain. Therefore, it is difficult for therapeutic drugs penetrate BBB reach brain, this affects their efficacy. Nanoparticles (NPs) can be used as drug carriers also known nanoparticle-based delivery systems (NDDSs). These not only increase stability but facilitate crossing through improve In article, we provided overview types administration routes NPs, highlighted preclinical clinical studies NDDSs neurodegenerative diseases, summarized combined strategies management diseases. Finally, prospects challenges recent basic research were discussed. Above all, provide inspiring strategy treatment

Language: Английский

Citations

40
Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies DOI Creative Commons
Sagar Gaikwad, Sudipta Senapati, Md. Anzarul Haque

et al.

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 20(1), P. 709 - 727

Published: Oct. 9, 2023

Abstract Aging, tau pathology, and chronic inflammation in the brain play crucial roles synaptic loss, neurodegeneration, cognitive decline tauopathies, including Alzheimer's disease. Senescent cells accumulate aging brain, accelerate process, promote tauopathy progression through their abnormal inflammatory secretome known as senescence‐associated secretory phenotype (SASP). Tau oligomers (TauO)—the most neurotoxic species—are to induce senescence SASP, which subsequently neuropathology, inflammation, oxidative stress, dysfunction, neuronal death, dysfunction. TauO, are associated with heterogeneity decline. However, underlying mechanisms driving disease remain largely unknown, impeding development of therapies for tauopathies. Based on clinical preclinical evidence, this review highlights critical role TauO neurodegeneration. We discuss key knowledge gaps potential strategies targeting treat Highlights Senescence, oligomeric (TauO), process contributing highlight target tauopathies while addressing gaps.

Language: Английский

Citations

31
Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders DOI Creative Commons
Fabiola De Marchi, Ivana Munitić,

Lea Vidatic

et al.

Biomedicines, Journal Year: 2023, Volume and Issue: 11(10), P. 2793 - 2793

Published: Oct. 14, 2023

Many potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases, such as Alzheimer's (AD) disease, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), well a seemingly distinct Niemann-Pick type C with primarily juvenile onset. This strongly argues for an overlap pathogenic mechanisms. The commonly researched include various cell subsets, microglia, peripheral macrophages, regulatory T cells (Tregs); the complement system; other soluble factors. In this review, we compare these diseases from clinical point of view highlight common pathways mechanisms protein aggregation, neurodegeneration, and/or neuroinflammation that could potentially lead to shared treatment strategies overlapping dysfunctions diseases. These approaches but not limited immunisation, cascade blockade, microbiome regulation, inhibition signal transduction, Treg boosting, stem transplantation.

Language: Английский

Citations

26
Blood–brain crosstalk: the roles of neutrophils, platelets, and neutrophil extracellular traps in neuropathologies DOI
Ming‐Li Chou, Babamale Olarewaju Abdulkareem, Tara L. Walker

et al.

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(9), P. 764 - 779

Published: July 25, 2023

Language: Английский

Citations

24
The therapeutic landscape of tauopathies: challenges and prospects DOI Creative Commons
Jeffrey L. Cummings, María Isabel González,

Martyn C. Pritchard

et al.

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

Published: Oct. 6, 2023

Abstract Tauopathies are a group of neurodegenerative disorders characterized by the aggregation microtubule-associated protein tau. Aggregates misfolded tau believed to be implicated in neuronal death, which leads range symptoms including cognitive decline, behavioral change, dementia, and motor deficits. Currently, there no effective treatments for tauopathies. There four clinical candidates phase III trials 16 II trials. While currently approved, is increasing evidence suggest that various therapeutic approaches may slow progression tauopathies or improve symptoms. This review outlines landscape drugs (indexed through February 28, 2023) target pathology describes drug development as well those discovery preclinical phases. The also contains information on notable programs inactive have been discontinued from development.

Language: Английский

Citations

22
Taming neuroinflammation in Alzheimer's disease: The protective role of phytochemicals through the gut−brain axis DOI Open Access

Yoonsu Kim,

Jinkyu Lim, Jisun Oh

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 178, P. 117277 - 117277

Published: Aug. 9, 2024

Language: Английский

Citations

14
Discovery of Effective Dual PROTAC Degraders for Neurodegenerative Disease-Associated Aggregates DOI
Wentao Zhu,

Wenqian Zhang,

Jian Chen

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(5), P. 3448 - 3466

Published: Feb. 15, 2024

The aggregation of specific proteins is a histopathological hallmark in various neurodegenerative diseases (NDs), among which Alpha-synuclein (α-Syn) and tau have received increased attention. targeted protein degradation (TPD) strategy has been studied the treatment NDs, but multitarget bifunctional molecules ignored. Herein, series effective dual PROTAC degraders were developed, could degrade α-Syn aggregates total simultaneously. effects evaluated vitro, results showed that T3 significantly knockdown efficiency with DC50 1.57 ± 0.55 4.09 0.90 μM, respectively. Further mechanistic exploration effect was mediated by ubiquitin–proteasome system (UPS). Additionally, therapeutic efficacy confirmed an MPTP-induced PD mouse model. Our suggest these PROTACs may provide potential for NDs.

Language: Английский

Citations

13
Computational insights into the cross-talk between medin and Aβ: implications for age-related vascular risk factors in Alzheimer’s disease DOI Creative Commons
Fengjuan Huang,

Xinjie Fan,

Ying Wang

et al.

Briefings in Bioinformatics, Journal Year: 2024, Volume and Issue: 25(2)

Published: Jan. 22, 2024

Abstract The aggregation of medin forming aortic medial amyloid is linked to arterial wall degeneration and cerebrovascular dysfunction. Elevated levels arteriolar are correlated with an increased presence vascular amyloid-β (Aβ) aggregates, a hallmark Alzheimer’s disease (AD) dementia. cross-interaction between Aβ results in the formation heterologous fibrils through co-aggregation cross-seeding processes both vitro vivo. However, comprehensive molecular understanding Aβ—two intrinsically disordered proteins—is critically lacking. Here, we employed atomistic discrete dynamics simulations systematically investigate self-association, also phenomenon these two proteins. Our demonstrated that were prone their mixture tended form β-sheet-rich hetero-aggregates. Aβ-medin hetero-aggregates did not hinder from recruiting additional peptides grow into larger aggregates. β-barrel oligomer intermediates observed self-aggregations present during co-aggregation. In simulations, preformed could recruit isolated monomers elongated β-sheets. Overall, our suggested may contribute pathological aggregation, given inherent amyloidogenic tendencies Aβ. Targeting medin, therefore, offer novel therapeutic approach preserving brain function aging AD by improving health.

Language: Английский

Citations

12
The function of sphingolipids in different pathogenesis of Alzheimer's disease: A comprehensive review DOI Open Access
Xinyi Wang, Huaqiang Li,

Yunjie Sheng

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 171, P. 116071 - 116071

Published: Jan. 6, 2024

Sphingolipids (SPLs) represent a highly diverse and structurally complex lipid class. The discussion of SPL metabolism-related issues is importance in understanding the neuropathological progression Alzheimer's disease (AD). AD characterized by accumulation extracellular deposits amyloid β-peptide (Aβ) intraneuronal aggregates microtubule-associated protein tau. Critical roles Aβ oligomer deposited ganglioside GM1 could be formed as "seed" from insoluble GAβ polymer initiating pathogenic process, while tau might also mediate SPLs their toxicity. interaction between ceramide α-Synuclein (α-Syn) accelerates aggregation ferroptosis exacerbates pathogenesis AD. For instance, reducing levels can mitigate α-Syn inhibit progression. Meanwhile, loss may expression APOE4 confer protection against AD, disrupts homeostasis. Moreover, heightened activation sphingomyelinase promotes signaling pathway, leading to exacerbated symptoms. Ferroptosis plays vital role pathological influencing Aβ, tau, APOE, α-Syn. Conversely, development manifestation SPLs. We are compiling emerging techniques (Derivatization IM-MS) sphingolipidomics, overcome challenges diagnosis treatment. In this review, we examined intricate neuro-mechanistic interactions α-Syn, ferroptosis, mediating onset Furthermore, our findings highlight potential targeting underexplored avenue for devising innovative therapeutic strategies

Language: Английский

Citations

11
Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration DOI Creative Commons
Wen Li, Jiayi Li

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

Published: March 26, 2024

Proteinopathy, defined as the abnormal accumulation of proteins that eventually leads to cell death, is one most significant pathological features neurodegenerative diseases. Tauopathies, represented by Alzheimer's disease (AD), and synucleinopathies, Parkinson's (PD), show similarities in multiple aspects. AD manifests extrapyramidal symptoms while dementia also a major sign advanced PD. We other researchers have sequentially shown cross-seeding phenomenon α-synuclein (α-syn) tau, reinforcing pathologies between synucleinopathies tauopathies. The highly overlapping clinical imply shared pathogenic mechanisms two groups disease. diagnostic therapeutic strategies seemingly appropriate for distinct may apply broader spectrum. Therefore, clear understanding overlaps divergences tauopathy synucleinopathy critical unraveling nature complicated associations among In this review, we discuss diverse characteristics tauopathies from aspects genetic causes, manifestations, progression potential common approaches targeting pathology, aim provide timely update setting scheme classification novel insights into development

Language: Английский

Citations

11