scholarly journals Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer’s disease mice

2022 ◽  
Vol 119 (3) ◽  
pp. e2115082119
Author(s):  
Min Hee Park ◽  
Kang Ho Park ◽  
Byung Jo Choi ◽  
Wan Hui Han ◽  
Hee Ji Yoon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Memory Function ◽  
Selective Inhibition ◽  
Acid Sphingomyelinase ◽  
Hippocampal Neurogenesis ◽  
Ghrelin Receptor ◽  
Dual Action

Alzheimer’s disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

scholarly journals Administration of Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI Improves Cognitive and Memory Function in the Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Hongwon Kim ◽  
Sumin Kim ◽  
Sang-jun Park ◽  
Gwoncheol Park ◽  
Hakdong Shin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Memory Function ◽  
Bifidobacterium Longum ◽  
Bifidobacterium Bifidum ◽  
Pathological Features ◽  
Bdnf Expression ◽  
Model Of Alzheimer’S Disease

Recent evidence indicates that gut microbiota could interact with the central nervous system and affect brain function, including cognition and memory. In this study, we investigated whether Bifidobacterium bifidum BGN4 (B. bifidum BGN4) and Bifidobacterium longum BORI (B. longum BORI) alleviated the pathological features in a mouse model of Alzheimer’s disease (AD). Administration of B. bifidum BGN4 and B. longum BORI effectively suppressed amyloidosis and apoptotic processes and improved synaptic plasticity by ameliorating the neuroinflammatory response and BDNF expression. Moreover, behavioral tests indicated that B. bifidum BGN4 and B. longum BORI attenuated the cognitive and memory disability of AD mice. Taken together, the present study highlights the therapeutic potential of B. bifidum BGN4 and B. longum BORI for suppressing the pathological features of AD.

scholarly journals Therapeutic Potential of Multifunctional Tacrine Analogues

2019 ◽  
Vol 17 (5) ◽  
pp. 472-490 ◽  
Author(s):  
Maja Przybyłowska ◽  
Szymon Kowalski ◽  
Krystyna Dzierzbicka ◽  
Iwona Inkielewicz-Stepniak
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Liver Toxicity ◽  
Potent Inhibitor ◽  
Therapeutic Potential ◽  
Treatment Strategies ◽  
Biological Properties ◽  
New Paradigm ◽  
Experimental Systems

Tacrine is a potent inhibitor of cholinesterases (acetylcholinesterase and butyrylcholinesterase) that shows limiting clinical application by liver toxicity. In spite of this, analogues of tacrine are considered as a model inhibitor of cholinesterases in the therapy of Alzheimer’s disease. The interest in these compounds is mainly related to a high variety of their structure and biological properties. In the present review, we have described the role of cholinergic transmission and treatment strategies in Alzheimer’s disease as well as the synthesis and biological activity of several recently developed classes of multifunctional tacrine analogues and hybrids, which consist of a new paradigm to treat Alzheimer’s disease. We have also reported potential of these analogues in the treatment of Alzheimer’s diseases in various experimental systems.

scholarly journals Autophagy in Alzheimer’s disease pathogenesis: therapeutic potential and future perspectives

2020 ◽  
Author(s):  
Zhigang Zhang ◽  
You-Qiang Song ◽  
Jie Tu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
The Elderly ◽  
Future Perspectives ◽  
Aβ Peptides ◽  
Evolutionarily Conserved ◽  
Amyloid Aβ ◽  
Folded Proteins

Alzheimer’s disease (AD) is a complex neurodegenerative disease in the elderly. It is the most common cause of dementia in human. AD is characterized by accumulation of abnormal protein aggregates including amyloid plaques (composed of beta-amyloid (Aβ) peptides) and neurofibrillary tangles (formed by hyper-phosphorylated tau protein). Besides, synaptic plasticity, neuroinflammation, calcium signaling etc. are found to be dysfunctional as well in AD patients. Autophagy is an evolutionarily conserved lysosome-dependent cellular event in eukaryotes. It is closely linked to the modulation of protein metabolism, through which damaged organelles and mis-folded proteins are degraded and then recycled to maintain protein homeostasis. Accumulating evidence has showed that impaired autophagy contributes to AD pathogenesis. In the present review, we highlight the role of autophagy, including bulk and selective autophagy, in regulating metabolic circuits in AD pathogenesis. We also discuss the potential and future perspectives of autophagy-inducing strategy in AD therapeutics.

scholarly journals Clemastine Ameliorates Myelin Deficits via Preventing Senescence of Oligodendrocytes Precursor Cells in Alzheimer’s Disease Model Mouse

2021 ◽  
Vol 9 ◽  
Author(s):  
Yuan-Yuan Xie ◽  
Ting-Ting Pan ◽  
De-en Xu ◽  
Xin Huang ◽  
Yong Tang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Short Term Memory ◽  
Therapeutic Potential ◽  
Disease Model ◽  
Model Mouse ◽  
Oligodendrocyte Precursor ◽  
Myelin Deficits ◽  
M1 Muscarinic

Disrupted myelin and impaired myelin repair have been observed in the brains of patients and various mouse models of Alzheimer’s disease (AD). Clemastine, an H1-antihistamine, shows the capability to induce oligodendrocyte precursor cell (OPC) differentiation and myelin formation under different neuropathological conditions featuring demyelination via the antagonism of M1 muscarinic receptor. In this study, we investigated if aged APPSwe/PS1dE9 mice, a model of AD, can benefit from chronic clemastine treatment. We found the treatment reduced brain amyloid-beta deposition and rescued the short-term memory deficit of the mice. The densities of OPCs, oligodendrocytes, and myelin were enhanced upon the treatment, whereas the levels of degraded MBP were reduced, a marker for degenerated myelin. In addition, we also suggest the role of clemastine in preventing OPCs from entering the state of cellular senescence, which was shown recently as an essential causal factor in AD pathogenesis. Thus, clemastine exhibits therapeutic potential in AD via preventing senescence of OPCs.

The Possible Role of Antioxidant Vitamin C in Alzheimer’s Disease Treatment and Prevention

2013 ◽  
Vol 28 (2) ◽  
pp. 120-125 ◽  
Author(s):  
Jae-Hyeok Heo ◽  
Hyon-Lee ◽  
Kyoung-Min Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vitamin C ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Acetylcholinesterase Activity ◽  
Antioxidant Vitamin ◽  
Treatment And Prevention ◽  
Current Article

Oxidative stress is suggested to play a major role in the pathogenesis of Alzheimer’s disease (AD). Among the antioxidants, vitamin C has been regarded as the most important one in neural tissue. It also decreases β-amyloid generation and acetylcholinesterase activity and prevents endothelial dysfunction by regulating nitric oxide, a newly discovered factor in the pathogenesis and progression of AD. However, clinical trials using antioxidants, including vitamin C, in patients with AD yielded equivocal results. The current article discusses the relevance of vitamin C in the cellular and molecular pathogenesis of AD and explores its therapeutic potential against this neurodegenerative disorder.

Possible role of DPP4 inhibitors to promote hippocampal neurogenesis in Alzheimer’s disease

2018 ◽  
Vol 26 (8) ◽  
pp. 670-675 ◽  
Author(s):  
Nehru Sai Suresh Chalichem ◽  
Pindiprolu S. S. Sai Kiran ◽  
Duraiswamy Basavan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Neurogenesis ◽  
Dpp4 Inhibitors

A bifunctional non-natural tetrapeptide modulates amyloid-beta peptide aggregation in the presence of Cu(ii)

Metallomics ◽  
2014 ◽  
Vol 6 (12) ◽  
pp. 2189-2192 ◽  
Author(s):  
Maripaz Márquez ◽  
Luis M. Blancas-Mejía ◽  
Adriana Campos ◽  
Luis Rojas ◽  
Gilberto Castañeda-Hernández ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Therapeutic Potential ◽  
Amyloid Beta Peptide ◽  
Peptide Aggregation ◽  
Beta Peptide ◽  
Aβ Aggregation

A novel bifunctional non-natural tetrapeptide, Met-Asp-d-Trp-Aib, is capable of binding copper, competing with amyloid-beta peptide (Aβ) for Cu(ii), and modulating Aβ aggregation. The study of this tetrapeptide provides further insights into the role of Cu(ii) in the Aβ aggregation pathway, and into the design of compounds with therapeutic potential for Alzheimer's disease.

scholarly journals Therapeutic Potential of Neu1 in Alzheimer’s Disease Via the Immune System

2021 ◽  
Vol 36 ◽  
pp. 153331752199614
Author(s):  
Aiza Khan ◽  
Sumit Das ◽  
Consolato Sergi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
Therapeutic Potential ◽  
Amyloid Plaques ◽  
Beta Amyloid ◽  
Underlying Mechanism ◽  
Amyloid Deposits ◽  
Potential Therapeutic Role

Alzheimer’s Disease (AD) is pathologically characterized by the accumulation of soluble oligomers causing extracellular beta-amyloid deposits in form of neuritic plaques and tau-containing intraneuronal neurofibrillary tangles in brain. One proposed mechanism explaining the formation of these proteins is impaired phagocytosis by microglia/macrophages resulting in defective clearance of soluble oligomers of beta-amyloid stimulating aggregation of amyloid plaques subsequently causing AD. However, research indicates that activating macrophages in M2 state may reduce toxic oligomers. NEU1 mutation is associated with a rare disease, sialidosis. NEU1 deficiency may also cause AD-like amyloidogenic process. Amyloid plaques have successfully been reduced using NEU1.Thus, NEU1 is suggested to have therapeutic potential for AD, with lysosomal exocytosis being suggested as underlying mechanism. Studies however demonstrate that NEU1 may activate macrophages in M2 state, which as noted earlier, is crucial to reducing toxic oligomers. In this review, authors discuss the potential therapeutic role of NEU1 in AD via immune system.

scholarly journals The Use of Antimicrobial and Antiviral Drugs in Alzheimer’s Disease

2020 ◽  
Vol 21 (14) ◽  
pp. 4920
Author(s):  
Umar H. Iqbal ◽  
Emma Zeng ◽  
Giulio M. Pasinetti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Physiological Role ◽  
Antiviral Drugs ◽  
Tau Proteins ◽  
The Brain ◽  
Potential Therapeutics

The aggregation and accumulation of amyloid-β plaques and tau proteins in the brain have been central characteristics in the pathophysiology of Alzheimer’s disease (AD), making them the focus of most of the research exploring potential therapeutics for this neurodegenerative disease. With success in interventions aimed at depleting amyloid-β peptides being limited at best, a greater understanding of the physiological role of amyloid-β peptides is needed. The development of amyloid-β plaques has been determined to occur 10–20 years prior to AD symptom manifestation, hence earlier interventions might be necessary to address presymptomatic AD. Furthermore, recent studies have suggested that amyloid-β peptides may play a role in innate immunity as an antimicrobial peptide. These findings, coupled with the evidence of pathogens such as viruses and bacteria in AD brains, suggests that the buildup of amyloid-β plaques could be a response to the presence of viruses and bacteria. This has led to the foundation of the antimicrobial hypothesis for AD. The present review will highlight the current understanding of amyloid-β, and the role of bacteria and viruses in AD, and will also explore the therapeutic potential of antimicrobial and antiviral drugs in Alzheimer’s disease.

scholarly journals The Role of Chemokines in Alzheimer's Disease

2020 ◽  
Vol 20 (9) ◽  
pp. 1383-1390 ◽  
Author(s):  
Adrian Jorda ◽  
Juan Campos-Campos ◽  
Antonio Iradi ◽  
Martin Aldasoro ◽  
Constanza Aldasoro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Senile Plaques ◽  
Large Family ◽  
Inflammatory Cells ◽  
Cytokines And Chemokines ◽  
Amyloid Aggregates

Objective: The most common multifactorial neurodegenerative disorder occurring in old age is Alzheimer’s disease. The neuropathological hallmarks of that disorder are amyloid plaques with the presence of β -amyloid aggregates, intraneuronal tau protein tangles, and chronic inflammation. Brain cells such as microglia and astrocytes are inflammatory cells associated with Alzheimer’s disease and involved in the production of inflammatory mediators, such as cytokines and chemokines. Chemokines consist of a large family of protein mediators with low molecular weight, which able to control the migration and residence of all immune cells. In pathological conditions, such as Alzheimer’s disease, chemokines contribute to the inflammatory response by recruiting T cells and controlling microglia/ macrophages activation. Methods: The present study focuses on the role that chemokines and their receptors play in Alzheimer's disease and in processes such as inflammation and oxidative stress. Results: Chemokines are important mediators in AD and inflammation. They promote Aβ deposition and TAU hyperphosphorylation aggravating and increasing the progression of AD. Moreover, they affect the processing of senile plaques and produce abnormal TAU phosphorylation. Conclusion: There is no cure for AD but the therapeutic potential of chemokines to control the development of the disease may be a field of study to consider in the future.

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