scholarly journals Exploring the Efficacy of Anti-amyloid-β Therapeutics in Treating Alzheimer Disease

2022 ◽  
Vol 2 ◽  
Author(s):  
Ciara Downey ◽  
Keyword(s):  
Alzheimer Disease ◽  
Clinical Symptoms ◽  
Focal Point ◽  
Passive Immunization ◽  
Amyloid Β ◽  
Clinical Results ◽  
Aβ Oligomers ◽  
Current Therapies ◽  
Differential Selectivity ◽  
Amyloid Cascade

Alzheimer Disease (AD) is the most prevalent cause of dementia, characterized by initial memory impairment and progressive cognitive decline. The exact cause of AD is not yet completely understood. However, the presence of neurotoxic amyloid-beta (Aβ) peptides in the brain is often cited as the main causative agent in AD pathogenesis. In accordance with the amyloid hypothesis, Aβ accumulation initially occurs 15-20 years prior to the development of clinical symptoms. Current therapies focus on the prodromal and preclinical stages of AD due to past treatment failures involving patients with mild to moderate AD. Passive immunization via exogenous monoclonal antibodies (mAbs) administration has emerged as a promising anti-Aβ treatment in AD. This is reinforced by the recent approval of the mAb, aducanumab. mAbs have differential selectivity in their epitopes, each recognising different conformations of Aβ. In this way, various Aβ accumulative species can be targeted. mAbs directed against Aβ oligomers, the most neurotoxic species, are producing encouraging clinical results. Through understanding the process by which mAbs target the amyloid cascade, therapeutics could be developed to clear Aβ, prevent its aggregation, or reduce its production. This review examines the clinical efficacy evidence from previous clinical trials with anti-Aβ therapeutics, in particular, the mAbs. Future therapies are expected to involve a combined-targeted approach to the multiple mechanisms of the amyloid cascade in a particular stage or disease phenotype. Additional studies of presymptomatic AD will likely join ongoing prevention trials, in which mAbs will continue to serve as the focal point.

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

scholarly journals Current and Future Treatments in Alzheimer Disease: An Update

2020 ◽  
Vol 12 ◽  
pp. 117957352090739 ◽  
Author(s):  
Konstantina G Yiannopoulou ◽  
Sokratis G Papageorgiou
Keyword(s):  
Alzheimer Disease ◽  
Clinical Symptoms ◽  
Neurofibrillary Tangle ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Amyloid Β ◽  
Cell Therapies ◽  
Novel Biomarkers ◽  
Disease Modifying ◽  
Underlying Mechanisms

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

scholarly journals Topographic Distribution of Amyloid-β, Tau, and Atrophy in Patients With Behavioral/Dysexecutive Alzheimer Disease

Neurology ◽  
2020 ◽  
Vol 96 (1) ◽  
pp. e81-e92
Author(s):  
Joseph Therriault ◽  
Tharick A. Pascoal ◽  
Melissa Savard ◽  
Andrea L. Benedet ◽  
Mira Chamoun ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Clinical Symptoms ◽  
Characteristic Curve ◽  
Tertiary Care ◽  
Amyloid Β ◽  
Executive Dysfunction ◽  
Anterior Cingulate ◽  
Amyloid Pet ◽  
Clinical Criteria ◽  
Tau Pet

ObjectiveTo determine the associations between amyloid-PET, tau-PET, and atrophy with the behavioral/dysexecutive presentation of Alzheimer disease (AD), how these differ from amnestic AD, and how they correlate to clinical symptoms.MethodsWe assessed 15 patients with behavioral/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 patients with disease severity– and age-matched amnestic AD and a group of 131 cognitively unimpaired (CU) elderly individuals. All participants were evaluated with amyloid-PET with [18F]AZD4694, tau-PET with [18F]MK6240, MRI, and neuropsychological testing.ResultsVoxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioral/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate, and frontal insular cortices in contrast to amnestic AD. No differences were observed in the distribution of amyloid-PET or atrophy as determined by voxel-based morphometry. Voxelwise area under the receiver operating characteristic curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate, and frontal insular cortices were best able to differentiate between behavioral/dysexecutive and amnestic AD (area under the curve 0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction.ConclusionsOur results provide evidence of frontal cortical involvement of tau pathology in behavioral/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome.

The Pathogenesis Mechanism, Structure Properties, Potential Drugs and Therapeutic Nano-particles Against the Small Oligomers of Amyloid-β

2020 ◽  
Vol 20 ◽  
Author(s):  
Ke Wang ◽  
Liu Na ◽  
Mojie Duan
Keyword(s):  
Structural Information ◽  
Amyloid Β ◽  
Nano Particles ◽  
Aβ Oligomers ◽  
Toxic Species ◽  
Therapeutic Molecules ◽  
To Come ◽  
Come Into The Market ◽  
Amyloid Cascade ◽  
Structure Properties

: Alzheimer’s Disease (AD) is a devastating neurodegenerative disease affects millions of people in the world. The abnormal aggregation of amyloid b protein (Aβ) is regarded as the key event in AD onset. Meanwhile, the Aβ oligomers are believed to be the most toxic species of Aβ. Recent studies show that the Aβ dimers, which are the smallest form of Aβ oligomers, also have the neurotoxicity in the absence of other oligomers in physiological conditions. In this review we focus on the pathogenesis, structure and potential therapeutic molecules against small Aβ oligomers, as well as the nano-particles (NPs) in the treatment of AD. In this review, we firstly focus on the pathogenic mechanism of Aβ oligomers, especially the Aβ dimers. The toxicity of Aβ dimer or oligomers which attributes to the interactions with various receptors and the disruption of membrane or intracellular environments were introduced. Then the structure properties of Aβ dimers and oligomers are summarized. Although some structural information such as the secondary structure content are characterized by experimental technologies, the full detailed structures are still absent. Following that, the small molecules targeting Aβ dimers or oligomers are collected, nevertheless, all of these ligands are failed to come into the market, rising controversy of the Aβ-related “amyloid cascade hypothesis”. At last, the recent progresses about the nano-particles as the potential drugs or the drug delivery to the Aβ oligomers are present.

scholarly journals Roles of Stem Cells in the Treatment of Alzheimer’s Disease

2020 ◽  
Author(s):  
Yasaman Ebrahimikia ◽  
Shahram Darabi ◽  
Farzad Rajaei
Keyword(s):  
Stem Cells ◽  
Alzheimer Disease ◽  
Neurological Diseases ◽  
Amyloid Β ◽  
Cell Types ◽  
The Body ◽  
Undifferentiated Cells ◽  
Current Therapies ◽  
Financial Burdens ◽  
Different Cell Types

Introduction: Alzheimer disease (AD), known to be a leading cause of dementia that causes heavy social and financial burdens worldwide, characterized by progressive loss of neurons and synaptic connectivity after depositions of amyloid-β (Aβ) protein.AD manifests as an impaired ability to comprehend or use words, poor coordination and gait, and impaired executive functions in the realms of planning, ordering and making judgments. Generally, classification of AD includes familial and sporadic AD. Current therapies for AD patients can only alleviate symptoms, but cannot deter the neural degeneration, thus providing no long-term recovery. Stem cells are undifferentiated cells that have a potential to produce many different cell types in the body. A vast amount of data indicates the potential of stem cell therapy for various neurological diseases. Several studies revealed that neurons and glial cells have successfully been differentiated from various stem cells. Thus, in this article, we review the treatment of Alzheimer\ disease by various types of stem cells.

Challenging the Amyloid Cascade Hypothesis: Senile Plaques and Amyloid-β as Protective Adaptations to Alzheimer Disease

2004 ◽  
Vol 1019 (1) ◽  
pp. 1-4 ◽  
Author(s):  
HYOUNG-GON LEE ◽  
GEMMA CASADESUS ◽  
XIONGWEI ZHU ◽  
ATSUSHI TAKEDA ◽  
GEORGE PERRY ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Amyloid Cascade Hypothesis ◽  
Amyloid Cascade

scholarly journals Modulation of Lipid Kinase PI4KIIα Activity and Lipid Raft Association of Presenilin 1 Underlies γ-Secretase Inhibition by Ginsenoside (20S)-Rg3

2013 ◽  
Vol 288 (29) ◽  
pp. 20868-20882 ◽  
Author(s):  
Min Suk Kang ◽  
Seung-Hoon Baek ◽  
Yoon Sun Chun ◽  
A. Zenobia Moore ◽  
Natalie Landman ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Clinical Symptoms ◽  
Amyloid Β ◽  
Presenilin 1 ◽  
Amyloid Β Peptide ◽  
Lipid Kinase ◽  
Rate Limiting Step ◽  
Secretase Activity ◽  
Phosphatidylinositol 4 ◽  
Rate Limiting

Amyloid β-peptide (Aβ) pathology is an invariant feature of Alzheimer disease, preceding any detectable clinical symptoms by more than a decade. To this end, we seek to identify agents that can reduce Aβ levels in the brain via novel mechanisms. We found that (20S)-Rg3, a triterpene natural compound known as ginsenoside, reduced Aβ levels in cultured primary neurons and in the brains of a mouse model of Alzheimer disease. The (20S)-Rg3 treatment induced a decrease in the association of presenilin 1 (PS1) fragments with lipid rafts where catalytic components of the γ-secretase complex are enriched. The Aβ-lowering activity of (20S)-Rg3 directly correlated with increased activity of phosphatidylinositol 4-kinase IIα (PI4KIIα), a lipid kinase that mediates the rate-limiting step in phosphatidylinositol 4,5-bisphosphate synthesis. PI4KIIα overexpression recapitulated the effects of (20S)-Rg3, whereas reduced expression of PI4KIIα abolished the Aβ-reducing activity of (20S)-Rg3 in neurons. Our results substantiate an important role for PI4KIIα and phosphoinositide modulation in γ-secretase activity and Aβ biogenesis.

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