The role of TREM2 in Alzheimer’s disease: from the perspective of Tau DOI Creative Commons
Wendi Huang, Juan Huang, Nanqu Huang

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Nov. 8, 2023

Triggering receptor expressed on myeloid cells 2 (TREM2), a pattern recognition abundantly microglia, has been identified as one of the risk factors for Alzheimer’s disease (AD). Several studies have already demonstrated relationship between TREM2 and Tau. mutations altered expression play an important role in Tau phosphorylation. Furthermore, level phosphorylation is correlated with soluble (sTREM2). However, different stages AD, seems to varying effects pathology. The explicit interaction Tau, well how they affect AD pathology, remains unclear, there much evidence contrary that requires rational interpretation. Reviewing dual roles will help identify more appropriate development strategy targeting treat AD. Therefore, this review focuses interplay relation

Language: Английский

Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future DOI Creative Commons
Yun Zhang, Huaqiu Chen, Ran Li

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: June 30, 2023

Abstract Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as molecular driver pathogenesis progression. Aβ prime target for development AD therapy. However, repeated failures Aβ-targeted clinical trials have cast considerable doubt on amyloid cascade hypothesis whether drug followed correct course. recent successes targeted assuaged those doubts. In this review, we discussed evolution over last 30 years summarized application diagnosis modification. particular, extensively pitfalls, promises important unanswered questions regarding current anti-Aβ therapy, well strategies further study more feasible approaches optimization prevention treatment.

Language: Английский

Citations

364
Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles DOI Creative Commons
Betty M. Tijms, Eleonora M. Vromen,

Olav Mjaavatten

et al.

Nature Aging, Journal Year: 2024, Volume and Issue: 4(1), P. 33 - 47

Published: Jan. 9, 2024

Abstract Alzheimer’s disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity critical for AD drug development. Here we define subtypes using mass spectrometry proteomics in cerebrospinal fluid, based on 1,058 proteins, with different levels individuals ( n = 419) compared to controls 187). These had alterations protein that were associated distinct processes: subtype 1 was characterized by proteins related neuronal hyperplasticity; 2 innate immune activation; 3 RNA dysregulation; 4 choroid plexus dysfunction; and 5 blood–brain barrier impairment. Each specific genetic risk variants, example, enriched TREM2 R47H. Subtypes also differed clinical outcomes, survival times anatomical patterns of brain atrophy. results indicate highlight need personalized medicine.

Language: Английский

Citations

81
Molecular and metabolic heterogeneity of astrocytes and microglia DOI Creative Commons
Philip Hasel, William H. Aisenberg, F. Chris Bennett

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(4), P. 555 - 570

Published: March 22, 2023

Language: Английский

Citations

54
An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery DOI
Qin Huang, Ken Y. Chan, Jason Wu

et al.

Science, Journal Year: 2024, Volume and Issue: 384(6701), P. 1220 - 1227

Published: May 16, 2024

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden range of treatable genetic diseases. We engineered an adeno-associated virus (AAV) capsid, BI-hTFR1, binds transferrin receptor (TfR1), a protein expressed on blood-brain barrier. BI-hTFR1 was actively transported across brain endothelial cells and, relative to AAV9, provided 40 50 times greater reporter expression in CNS

Language: Английский

Citations

45
Emerging role of senescent microglia in brain aging-related neurodegenerative diseases DOI Creative Commons
Chan Rim, Min-Jung You, Minyeop Nahm

et al.

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

Published: Feb. 20, 2024

Abstract Brain aging is a recognized risk factor for neurodegenerative diseases like Alzheimer's disease, Parkinson's and amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), but the intricate interplay between brain pathogenesis of these conditions remains inadequately understood. Cellular senescence considered to contribute cellular dysfunction inflammaging. According threshold theory senescent cell accumulation, vulnerability associated with rates generation clearance within brain. Given role microglia in eliminating cells, accumulation may lead acceleration aging, contributing inflammaging increased diseases. In this review, we propose idea that microglia, which notably vulnerable could potentially serve as central catalyst progression The are emerging promising target mitigating

Language: Английский

Citations

35
Neuropathogenesis-on-chips for neurodegenerative diseases DOI Creative Commons
Sarnai Amartumur, Huong Mai Nguyen, Thuy Huynh

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 12, 2024

Abstract Developing diagnostics and treatments for neurodegenerative diseases (NDs) is challenging due to multifactorial pathogenesis that progresses gradually. Advanced in vitro systems recapitulate patient-like pathophysiology are emerging as alternatives conventional animal-based models. In this review, we explore the interconnected pathogenic features of different types ND, discuss general strategy modelling NDs using a microfluidic chip, introduce organoid-on-a-chip next advanced relevant model. Lastly, overview how these models being applied academic industrial drug development. The integration chips, stem cells, biotechnological devices promises provide valuable insights biomedical research developing diagnostic therapeutic solutions NDs.

Language: Английский

Citations

30
Passive immunotherapy for Alzheimer's disease DOI Creative Commons

Xiaoyi Guo,

Yan Li, Denghong Zhang

et al.

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 94, P. 102192 - 102192

Published: Jan. 14, 2024

Alzheimer's disease (AD) is the most common neurodegenerative characterized by cognitive impairment with few therapeutic options. Despite many failures in developing AD treatment during past 20 years, significant advances have been achieved passive immunotherapy of very recently. Here, we review characteristics, clinical trial data, and mechanisms action for monoclonal antibodies (mAbs) targeting key players pathogenesis, including amyloid-β (Aβ), tau neuroinflammation modulators. We emphasized efficacy lecanemab donanemab on cognition amyloid clearance patients phase III trials discussed factors that may contribute to side effects anti-Aβ mAbs. In addition, provided important information mAbs or inflammatory regulators trials, indicated against mid-region pathogenic potential AD. conclusion, pathogenesis offers a promising strategy effective treatment.

Language: Английский

Citations

25
Biomimetic Nanovesicles as a Dual Gene Delivery System for the Synergistic Gene Therapy of Alzheimer’s Disease DOI

Sujun Jiang,

Guoen Cai, Zhimin Yang

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(18), P. 11753 - 11768

Published: April 22, 2024

The association between dysfunctional microglia and amyloid-β (Aβ) is a fundamental pathological event increases the speed of Alzheimer's disease (AD). Additionally, pathogenesis AD intricate single drug may not be enough to achieve satisfactory therapeutic outcome. Herein, we reported facile effective gene therapy strategy for modulation function intervention Aβ anabolism by ROS-responsive biomimetic exosome-liposome hybrid nanovesicles (designated as TSEL). codelivery β-site amyloid precursor protein cleaving enzyme-1 (BACE1) siRNA (siBACE1) TREM2 plasmid (pTREM2) efficiently penetrate blood-brain barrier enhance accumulation at lesions with help exosomes homing ability angiopep-2 peptides. Specifically, an upregulation expression can reprogram from pro-inflammatory M1 phenotype anti-inflammatory M2 while also restoring its capacity phagocytose nerve repair function. In addition, reduces production plaques source knocking out BACE1 gene, which expected further effect AD. in vivo study suggests that TSEL through synergistic two drugs ameliorate APP/PS1 mice cognitive impairment regulating activated microglial phenotype, reducing Aβ, preventing retriggering neuroinflammation. This employs delivery dual nucleic acids, achieving AD, thus offering more options treatment

Language: Английский

Citations

25
Targeting the transferrin receptor to transport antisense oligonucleotides across the mammalian blood-brain barrier DOI
Scarlett J. Barker, Mai B. Thayer, Chaeyoung Kim

et al.

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(760)

Published: Aug. 14, 2024

Antisense oligonucleotides (ASOs) are promising therapeutics for treating various neurological disorders. However, ASOs unable to readily cross the mammalian blood-brain barrier (BBB) and therefore need be delivered intrathecally central nervous system (CNS). Here, we engineered a human transferrin receptor 1 (TfR1) binding molecule, oligonucleotide transport vehicle (OTV), tool ASO across BBB in TfR knockin (TfR mu/hu KI) mice nonhuman primates. Intravenous injection systemic delivery of OTV KI resulted sustained knockdown target RNA, Malat1 , multiple mouse CNS regions cell types, including endothelial cells, neurons, astrocytes, microglia, oligodendrocytes. In addition, enabled RNA quadriceps cardiac muscles, which difficult with alone. Systemically more uniform biodistribution profile greater compared bivalent, high-affinity antibody. cynomolgus macaques, an directed against MALAT1 displayed robust primate intrathecal dosing same unconjugated ASO. Our data support systemically as potential platform delivering therapeutic BBB.

Language: Английский

Citations

22
Targeting dysregulated lipid metabolism for the treatment of Alzheimer's disease and Parkinson's disease: Current advancements and future prospects DOI Creative Commons
Bin Tong,

Yaoqi Ba,

Zhengyang Li

et al.

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 196, P. 106505 - 106505

Published: April 19, 2024

Alzheimer's and Parkinson's diseases are two of the most frequent neurological diseases. The clinical features AD memory decline cognitive dysfunction, while PD mainly manifests as motor dysfunction such limb tremors, muscle rigidity abnormalities, slow gait. Abnormalities in cholesterol, sphingolipid, glycerophospholipid metabolism have been demonstrated to directly exacerbate progression by stimulating Aβ deposition tau protein tangles. Indirectly, abnormal lipids can increase burden on brain vasculature, induce insulin resistance, affect structure neuronal cell membranes. Abnormal lipid leads through inducing accumulation α-syn, mitochondria endoplasmic reticulum, ferroptosis. Great progress has made targeting abnormalities for treatment recent years, like metformin, insulin, peroxisome proliferator-activated receptors (PPARs) agonists, monoclonal antibodies apolipoprotein E (ApoE). This review comprehensively summarizes involvement dysregulated pathogenesis PD, application Lipid Monitoring, emerging regulatory drug targets. A better understanding lipidological bases may pave way developing effective prevention methods neurodegenerative disorders.

Language: Английский

Citations

17