Therapeutic Strategies Targeting Amyloid-β Receptors and Transporters in Alzheimer’s Disease

2021 ◽  
Vol 79 (4) ◽  
pp. 1429-1442
Author(s):  
Kejing Lao ◽  
Ruisan Zhang ◽  
Jing Luan ◽  
Yuelin Zhang ◽  
Xingchun Gou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rational Design ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
Membrane Receptors ◽  
Economic Costs ◽  
Medical Problems ◽  
Major Mechanism ◽  
Neurotoxic Effects

Alzheimer’s disease (AD) is a chronic neurodegenerative disease that has been recognized as one of the most intractable medical problems with heavy social and economic costs. Amyloid-β (Aβ) has been identified as a major factor that participates in AD progression through its neurotoxic effects. The major mechanism of Aβ-induced neurotoxicity is by interacting with membrane receptors and subsequent triggering of aberrant cellular signaling. Besides, Aβ transporters also plays an important role by affecting Aβ homeostasis. Thus, these Aβ receptors and transporters are potential targets for the development of AD therapies. Here, we summarize the reported therapeutic strategies targeting Aβ receptors and transporters to provide a molecular basis for future rational design of anti-AD agents.

scholarly journals Exploring Aβ Proteotoxicity and Therapeutic Candidates Using Drosophila melanogaster

2021 ◽  
Vol 22 (19) ◽  
pp. 10448
Author(s):  
Greta Elovsson ◽  
Liza Bergkvist ◽  
Ann-Christin Brorsson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drosophila Melanogaster ◽  
Model Organism ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
Disease Genes ◽  
Amyloid Β Peptide ◽  
Drug Candidates ◽  
Human Disease Genes

Alzheimer’s disease is a widespread and devastating neurological disorder associated with proteotoxic events caused by the misfolding and aggregation of the amyloid-β peptide. To find therapeutic strategies to combat this disease, Drosophila melanogaster has proved to be an excellent model organism that is able to uncover anti-proteotoxic candidates due to its outstanding genetic toolbox and resemblance to human disease genes. In this review, we highlight the use of Drosophila melanogaster to both study the proteotoxicity of the amyloid-β peptide and to screen for drug candidates. Expanding the knowledge of how the etiology of Alzheimer’s disease is related to proteotoxicity and how drugs can be used to block disease progression will hopefully shed further light on the field in the search for disease-modifying treatments.

Therapeutic Strategies Targeting Amyloid-β in Alzheimer’s Disease

2019 ◽  
Vol 16 (5) ◽  
pp. 418-452 ◽  
Author(s):  
Lídia Pinheiro ◽  
Célia Faustino
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Senile Plaques ◽  
Symptomatic Relief ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
App Processing

Alzheimer’s disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-β (Aβ) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD. Amyloidosis has been implicated in the depression of acetylcholine synthesis and release, overactivation of N-methyl-D-aspartate (NMDA) receptors and increased intracellular calcium levels that result in excitotoxic neuronal degeneration. Current drugs used in AD treatment are either cholinesterase inhibitors or NMDA receptor antagonists; however, they provide only symptomatic relief and do not alter the progression of the disease. Aβ is the product of Amyloid Precursor Protein (APP) processing after successive cleavage by β- and γ-secretases while APP proteolysis by α-secretase results in non-amyloidogenic products. According to the amyloid cascade hypothesis, Aβ dyshomeostasis results in the accumulation and aggregation of Aβ into soluble oligomers and insoluble fibrils. The former are synaptotoxic and can induce tau hyperphosphorylation while the latter deposit in senile plaques and elicit proinflammatory responses, contributing to oxidative stress, neuronal degeneration and neuroinflammation. Aβ-protein-targeted therapeutic strategies are thus a promising disease-modifying approach for the treatment and prevention of AD. This review summarizes recent findings on Aβ-protein targeted AD drugs, including β-secretase inhibitors, γ-secretase inhibitors and modulators, α-secretase activators, direct inhibitors of Aβ aggregation and immunotherapy targeting Aβ, focusing mainly on those currently under clinical trials.

Target Enzyme in Alzheimer’s Disease: Acetylcholinesterase Inhibitors

2019 ◽  
Vol 19 (4) ◽  
pp. 264-275 ◽  
Author(s):  
Mridula Saxena ◽  
Ragini Dubey
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Molecule ◽  
Rational Design ◽  
Large Population ◽  
Antioxidant Properties ◽  
Radical Scavenging ◽  
Amyloid Β ◽  
Learning Ability ◽  
Hybrid Molecules

Alzheimer’s Disease (AD), affecting a large population worldwide is characterized by the loss of memory and learning ability in the old population. The enzyme Acetylcholinesterase Enzyme (AChE) is the key enzyme in the hydrolysis of the neurotransmitter acetylcholine and is also the target of most of the clinically used drugs for the treatment of AD but these drugs provide only symptomatic treatment and have the limitation of loss of therapeutic efficacy with time. The development of different strategies targeting the AChE enzyme along with other targets like Butyl Cholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals antioxidant properties and free radical scavenging capacity has been focused in recent years. Literature search was conducted for the molecules and their rational design which have shown inhibition for AChE and the other abovementioned targets. Several hybrid molecules incorporating the main sub-structures derived from diverse chemotypes like acridine, quinoline, carbamates, and other heterocyclic analogs have shown desired pharmacological activity with a good profile in a single molecule. It is followed by optimization of the activity through structural modifications guided by structure-activity relationship studies. It has led to the discovery of novel molecules 17b, 20, and 23 with desired AChE inhibition along with desirable activity against other abovementioned targets for further pre-clinical studies.

scholarly journals Rational design of a conformation-specific antibody for the quantification of Aβ oligomers

2020 ◽  
Vol 117 (24) ◽  
pp. 13509-13518 ◽  
Author(s):  
Francesco A. Aprile ◽  
Pietro Sormanni ◽  
Marina Podpolny ◽  
Shianne Chhangur ◽  
Lisa-Maria Needham ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Rational Design ◽  
Design Method ◽  
Amyloid Β ◽  
In Vitro Assays ◽  
Aβ Oligomers ◽  
Detection And Quantification

Protein misfolding and aggregation is the hallmark of numerous human disorders, including Alzheimer’s disease. This process involves the formation of transient and heterogeneous soluble oligomers, some of which are highly cytotoxic. A major challenge for the development of effective diagnostic and therapeutic tools is thus the detection and quantification of these elusive oligomers. Here, to address this problem, we develop a two-step rational design method for the discovery of oligomer-specific antibodies. The first step consists of an “antigen scanning” phase in which an initial panel of antibodies is designed to bind different epitopes covering the entire sequence of a target protein. This procedure enables the determination through in vitro assays of the regions exposed in the oligomers but not in the fibrillar deposits. The second step involves an “epitope mining” phase, in which a second panel of antibodies is designed to specifically target the regions identified during the scanning step. We illustrate this method in the case of the amyloid β (Aβ) peptide, whose oligomers are associated with Alzheimer’s disease. Our results show that this approach enables the accurate detection and quantification of Aβ oligomers in vitro, and inCaenorhabditis elegansand mouse hippocampal tissues.

scholarly journals Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Lin Jia ◽  
Juan Piña-Crespo ◽  
Yonghe Li
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rational Design ◽  
Signal Transduction Pathway ◽  
Amyloid Β ◽  
Synaptic Loss ◽  
Cellular Processes ◽  
And Function ◽  
The Brain ◽  
Blood Brain Barrier Integrity

AbstractAlzheimer’s disease (AD) is an aging-related neurological disorder characterized by synaptic loss and dementia. Wnt/β-catenin signaling is an essential signal transduction pathway that regulates numerous cellular processes including cell survival. In brain, Wnt/β-catenin signaling is not only crucial for neuronal survival and neurogenesis, but it plays important roles in regulating synaptic plasticity and blood-brain barrier integrity and function. Moreover, activation of Wnt/β-catenin signaling inhibits amyloid-β production and tau protein hyperphosphorylation in the brain. Critically, Wnt/β-catenin signaling is greatly suppressed in AD brain via multiple pathogenic mechanisms. As such, restoring Wnt/β-catenin signaling represents a unique opportunity for the rational design of novel AD therapies.

Critical Review of the Alzheimer’s Disease Non-Transgenic Models: Can They Contribute to Disease Treatment?

2020 ◽  
pp. 1-24
Author(s):  
Julio A. Flores-Cuadra ◽  
Alanna Madrid ◽  
Patricia L. Fernández ◽  
Ambar R. Pérez-Lao ◽  
Diana C. Oviedo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Critical Review ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
Intervention Strategies ◽  
Transgenic Models ◽  
Preclinical Research ◽  
Disease Treatment

Alzheimer’s disease (AD) is a growing neurodegenerative disease without effective treatments or therapies. Despite the use of different approaches and an extensive variety of genetic amyloid based models, therapeutic strategies remain elusive. AD is characterized by three main pathological hallmarks that include amyloid-β plaques, neurofibrillary tangles, and neuroinflammatory processes; however, many other pathological mechanisms have been described in the literature. Nonetheless, the study of the disease and the screening of potential therapies is heavily weighted toward the study of amyloid-β transgenic models. Non-transgenic models may aid in the study of complex pathological states and provide a suitable complementary alternative to evaluating therapeutic biomedical and intervention strategies. In this review, we evaluate the literature on non-transgenic alternatives, focusing on the use of these models for testing therapeutic strategies, and assess their contribution to understanding AD. This review aims to underscore the need for a shift in preclinical research on intervention strategies for AD from amyloid-based to alternative, complementary non-amyloid approaches.

scholarly journals Extracellular protein components of amyloid plaques and their roles in Alzheimer’s disease pathology

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
M. Mahafuzur Rahman ◽  
Christofer Lendel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Extracellular Proteins ◽  
Comprehensive Overview ◽  
Neurotoxic Effects ◽  
Protein Components ◽  
Living Organisms ◽  
The Many

AbstractAlzheimer’s disease (AD) is pathologically defined by the presence of fibrillar amyloid β (Aβ) peptide in extracellular senile plaques and tau filaments in intracellular neurofibrillary tangles. Extensive research has focused on understanding the assembly mechanisms and neurotoxic effects of Aβ during the last decades but still we only have a brief understanding of the disease associated biological processes. This review highlights the many other constituents that, beside Aβ, are accumulated in the plaques, with the focus on extracellular proteins. All living organisms rely on a delicate network of protein functionality. Deposition of significant amounts of certain proteins in insoluble inclusions will unquestionably lead to disturbances in the network, which may contribute to AD and copathology. This paper provide a comprehensive overview of extracellular proteins that have been shown to interact with Aβ and a discussion of their potential roles in AD pathology. Methods that can expand the knowledge about how the proteins are incorporated in plaques are described. Top-down methods to analyze post-mortem tissue and bottom-up approaches with the potential to provide molecular insights on the organization of plaque-like particles are compared. Finally, a network analysis of Aβ-interacting partners with enriched functional and structural key words is presented.

scholarly journals A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tatsuya Ikenoue ◽  
Francesco A. Aprile ◽  
Pietro Sormanni ◽  
Francesco S. Ruggeri ◽  
Michele Perni ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rational Design ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Disordered Proteins ◽  
Amyloid Β Peptide ◽  
Model Of Alzheimer’S Disease ◽  
Worm Model

Abstract Bicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31–42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer’s disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.

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