Review
Medicine, Research & Experimental
Alberto Fernando Oliveira Justo, Eliana Cristina de Brito Toscano, Daniela Souza Farias-Itao, Claudia Kimie Suemoto
Summary: Alzheimer's disease (AD) is the leading cause of dementia worldwide, and the deposition of beta-amyloid in the brain is partially responsible for its etiology. Despite extensive research, current treatments for AD are ineffective. This study systematically reviewed the use of phosphodiesterase 5 inhibitors (PDE5i) in rodent models with beta-amyloid accumulation and found that PDE5i was efficient in reducing beta-amyloid levels in the hippocampi and preventing cognitive decline. However, further experimental studies are needed to evaluate the molecular mechanisms of PDE5i in beta-amyloid removal in both male and female animals.
Article
Chemistry, Multidisciplinary
Qianhua Feng, Ning Wang, Xueli Zhang, Yuying Mei, Rongkun Fu, Jing Chen, Xiaomin Yuan, Shuaiqi Yang, Zhenzhong Zhang, Hongjuan Zhao, Lei Wang
Summary: A nanoparticle cluster is designed to prevent amyloid fibrillation by binding to amyloid-beta through a multivalent binding strategy. The cluster decomposes into smaller nanoparticles upon reaching the Alzheimer's disease nidus, which bind strongly to amyloid-beta and disrupt amyloid interactions. The resulting nanoparticle-amyloid composite delivers rapamycin to microglia, improving the immune dysfunction and removing amyloid-beta, ultimately rescuing memory deficits in Alzheimer's disease.
Article
Chemistry, Multidisciplinary
Yijing Tang, Dong Zhang, Xiong Gong, Jie Zheng
Summary: This study demonstrates a rational design strategy of an amyloid-aggregation-induced emission (AIE)-active molecule, G7-TBA, which serves as a multiple-target, dual-function amyloid probe and modulator for detecting, monitoring, and altering amyloid aggregation of different amyloid proteins.
ADVANCED FUNCTIONAL MATERIALS
(2022)
Review
Medicine, Research & Experimental
Yilan Xu, Manna Zhao, Dongming Zhou, Tingting Zheng, Heng Zhang
Summary: Nanomaterials, due to their small size, can cross the blood-brain barrier and achieve high bioavailability when modified for specific cell targeting; they show promising potential as agents for treating neurodegenerative diseases, particularly in Alzheimer's disease, with studies indicating the potential for slowing down disease progression through enhanced therapeutic effects.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Review
Biochemistry & Molecular Biology
Maria Rosaria Tropea, Walter Gulisano, Valeria Vacanti, Ottavio Arancio, Daniela Puzzo, Agostino Palmeri
Summary: This review provides an overview of the interaction between the nitric oxide /cGMP pathway and A beta in both healthy and diseased brain, offering new insights into the pathophysiology of Alzheimer's disease. The focus is on the synaptic mechanisms underlying the interplay between A beta and the cGMP pathway, and how this balance is disrupted in Alzheimer's disease.
FREE RADICAL BIOLOGY AND MEDICINE
(2022)
Review
Chemistry, Multidisciplinary
Shima Tajahmadi, Hossein Molavi, Farhad Ahmadijokani, Amir Shamloo, Akbar Shojaei, Mohammad Sharifzadeh, Mashallah Rezakazemi, Ali Fatehizadeh, Tejraj M. Aminabhavi, Mohammad Arjmand
Summary: Beta-amyloid (Al3) peptide is a key biomarker of Alzheimer's disease (AD), and monitoring its levels is crucial for early diagnosis, prevention, and treatment. Recent attention has focused on the potential of metal-organic frameworks (MOFs) for AD diagnosis and treatment. This review discusses the latest advances in using MOFs for early detection of AD biomarkers, detection of metal ions in the brain, and imaging of Al3 plaques.
JOURNAL OF CONTROLLED RELEASE
(2023)
Article
Neurosciences
Qian Shi, Cheng Chang, Afaf Saliba, Manzoor A. Bhat
Summary: This study reveals the critical link between mTOR signaling and Trem2 regulation and lysosomal biogenesis in microglia. Activation of mTOR in microglia upregulates Trem2 expression, enhances Ab clearance, reduces spine loss, and improves cognitive function. However, in Alzheimer's disease, excessive activation of mTOR leads to decreased Trem2 expression, reduced Ab clearance, and increased Ab plaque burden.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Immunology
Wangyu Bi, Tong Lei, Shanglin Cai, Xiaoshuang Zhang, Yanjie Yang, Zhuangzhuang Xiao, Lei Wang, Hongwu Du
Summary: This review summarizes the role of astrocytes in Alzheimer's disease (AD) and explores the potential therapeutic strategies targeting astrocytes. Astrocytes play an important role in the pathogenesis of AD, and therapies targeting astrocytes have shown high efficacy.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2022)
Article
Chemistry, Analytical
G. S. Meghana, D. Gowda, Saravana Babu Chidambaram, Riyaz Ali Osmani
Summary: The pathology of Alzheimer's disease (AD) is driven by the imbalance in A beta production, clearance, and deposition in the brain. Current treatment strategies focus on symptomatic management rather than specific targets. The neurotoxic potential of A beta oligomerisation has led to research on preventing its aggregation. Nano-technology based delivery systems show promise in delivering drugs across the blood brain barrier for effective management of AD.
VIBRATIONAL SPECTROSCOPY
(2023)
Article
Medicine, Research & Experimental
Sujin Kim, Yunkwon Nam, Soo Jung Shin, Ritu Prajapati, Seong Min Shin, Min-Jeong Kim, Hyeon Soo Kim, Seol Hwa Leem, Tae-Jin Kim, Yong Ho Park, Jwa-Jin Kim, Jae Sue Choi, Minho Moon
Summary: This study demonstrates that Uncaria rhynchophylla (UR) has significant effects on the aggregation and dissociation of both A beta and tau, potentially offering a therapeutic option for Alzheimer's disease.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Immunology
Zhiyu Wang, Donald F. Weaver
Summary: Alzheimer's disease is a neurodegenerative disorder characterized by the progressive deterioration of multiple cognitive functions. Microglial cells play a crucial role in the pathogenesis of Alzheimer's disease through the recognition and response to misfolded proteins like beta-amyloid and tau. These proteins contribute to neuroinflammation and neurotoxicity, while microglia's primary function is to maintain brain homeostasis and synaptic integrity. However, prolonged activation of microglia can be harmful. This review discusses the role of microglia in Alzheimer's disease pathogenesis and explores potential drug candidates targeting microglial receptors.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2022)
Review
Pharmacology & Pharmacy
Ana R. Monteiro, Daniel J. Barbosa, Fernando Remiao, Renata Silva
Summary: Alzheimer's disease is a prevalent neurodegenerative disease that affects millions of people worldwide. It is characterized by cognitive decline and degeneration of cholinergic neurons. The available therapies are limited, and the disease's pathogenesis is complex, involving the presence of neurofibrillary tangles and amyloid-beta peptide aggregates. Innovative multitarget therapeutical compounds are being developed to delay disease progression and restore cell function, and research on new insights and emerging disease-modifying drugs is ongoing.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Rathnam Mallesh, Juhee Khan, Prabir Kumar Gharai, Subhajit Ghosh, Shubham Garg, Mohammad Umar Arshi, Surajit Ghosh
Summary: The overproduction and deposition of amyloid-fi (Afi) aggregates are responsible for the development of Alzheimer's disease (AD). However, effective medications and detection agents for AD are still lacking. This study introduces a fluorescent probe called AR-14, which has the ability to cross the blood-brain barrier and selectively bind to Afi species. AR-14 shows strong fluorescence emission at a longer wavelength after binding with soluble and insoluble Afi deposits, making it a promising tool for in vitro and in vivo detection.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Pinky Gehlot, Sunil Kumar, Vivek Kumar Vyas, Bhanwar Singh Choudhary, Manish Sharma, Ruchi Malik
Summary: This paper reviews the use of guanidine-based novel BACE-1 inhibitors for the treatment and maintenance of Alzheimer's disease. Alzheimer's disease is an irreversible neurological disorder, and BACE-1 is an important target for its treatment. Inhibiting BACE-1 can prevent or reverse the progression of the disease.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Kathryn J. C. Watt, Richard M. Meade, Robert J. Williams, Jody M. Mason
Summary: This study identified five peptides that have inhibitory effects on the aggregation of Parkinson's disease (PD) related protein variants. These peptides not only reduce the aggregation of PD-associated proteins, but also show the same efficacy when incubated with other variants. Additionally, the optimized peptide 4554W(N6A) is highly effective against wild-type protein and several single-point mutant forms, providing a suitable baseline for further PD therapeutic research.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Michael S. Wolfe
Article
Biochemistry & Molecular Biology
Anijamol T. Philip, Sujan Devkota, Shweta Malvankar, Sanjay Bhattarai, Kathleen M. Meneely, Todd D. Williams, Michael S. Wolfe
Article
Chemistry, Multidisciplinary
Sanjay Bhattarai, Sujan Devkota, Kathleen M. Meneely, Minli Xing, Justin T. Douglas, Michael S. Wolfe
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2020)
Review
Chemistry, Medicinal
Michael S. Wolfe
MEDICINAL CHEMISTRY RESEARCH
(2020)
Article
Chemistry, Multidisciplinary
Apurba Bhattarai, Sujan Devkota, Sanjay Bhattarai, Michael S. Wolfe, Yinglong Miao
ACS CENTRAL SCIENCE
(2020)
Article
Biochemistry & Molecular Biology
Sujan Devkota, Todd D. Williams, Michael S. Wolfe
Summary: Systematic and quantitative analyses were conducted to study the effects of 14 FAD mutations on γ-secretase processing of APP substrates. All mutations resulted in inefficient processing of Aβ peptides longer than 45 residues. Certain mutations provided insights into the mechanism of processive proteolysis.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Review
Chemistry, Medicinal
Michael S. Wolfe
Summary: Familial Alzheimer's disease (FAD) is a rare genetic form of early-onset dementia caused by missense mutations in three genes related to Aβ and Aβ42. While treatments targeting Aβ and Aβ42 have been unsuccessful, recent findings suggest that FAD mutations play a key role in the deficient trimming of Aβ peptides, indicating a potential focus for future drug development.
MEDICINAL CHEMISTRY RESEARCH
(2021)
Article
Chemistry, Medicinal
Sanjay Bhattarai, Sujan Devkota, Michael S. Wolfe
Summary: The study describes a prototype substrate TMD mimetic that can trap transition states for endoproteolysis, TMD helix unwinding, and lateral gating of the substrate. The developed variants of this prototype are designed to allow visualization of different transition states, with the TMD mimetics exhibiting non-competitive inhibition and occupying both the exosite and the active site. These new probes serve as important structural tools for trapping various stages of substrate recognition and processing, aiding in rational drug design through cryo-electron microscopy studies with gamma-secretase.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Apurba Bhattarai, Sujan Devkota, Hung Nguyen Do, Jinan Wang, Sanjay Bhattarai, Michael S. Wolfe, Yinglong Miao
Summary: This study investigated the mechanism of tripeptide trimming of Aβ49 by gamma-secretase using a combination of biochemical experiments and Pep-GaMD simulations. The results showed that the efficiency of tripeptide trimming was similar for certain familial AD mutants, but diminished for others. The simulations revealed structural rearrangements of the enzyme and substrate, and the importance of a positively charged N-terminus for the trimming process.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Correction
Chemistry, Multidisciplinary
Apurba Bhattarai, Sujan Devkota, Hung Nguyen Do, Jinan Wang, Sanjay Bhattarai, Michael S. Wolfe, Yinglong Miao
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Editorial Material
Chemistry, Medicinal
Michael S. Wolfe
FUTURE MEDICINAL CHEMISTRY
(2022)
Article
Neurosciences
Masato Maesako, Mei C. Q. Houser, Yuliia Turchyna, Michael S. Wolfe, Oksana Berezovska
Summary: In this study, we used a novel imaging method to visualize the subcellular compartment where γ-secretase primarily cleaves C99 to generate Aβ in mouse cortical neurons. Our findings suggest that γ-secretase processes C99 mainly in low-pH compartments and Aβ is accumulated in the same subcellular loci. Additionally, we found a functional correlation between endo-lysosomal pH and cellular γ-secretase activity.
JOURNAL OF NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Lei Liu, Bianca M. Lauro, Michael S. Wolfe, Dennis J. Selkoe
Summary: The hydrophilic loop-1 of presenilin-1 is crucial for the processivity of gamma-secretase and its modulation by heterocyclic gamma-secretase modulators. Mutations in key amino acids within HL-1 affect the production of pathogenic A beta peptides. The GxxxG motif in the APP transmembrane region is also essential for gamma-secretase processivity. Together, these findings provide insights for designing new GSMs to reduce the production of amyloidogenic A beta peptides in AD.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)