Challenges and hopes for Alzheimer’s disease

Tatulian, Suren A.

doi:10.1016/j.drudis.2022.01.016

Cited by 163 publications

(98 citation statements)

References 210 publications

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“…About 70–80% of all dementia cases (over 55 million people worldwide, according to World Health Organization, WHO) correspond to Alzheimer’s disease (AD), which represents a progressive neurodegenerative disorder leading to brain atrophy and death (reviewed in ref. [ 1 , 2 ]). Due to increasing life expectancy in developed countries, AD is a global threat, lacking effective curative or preventive means despite the enormous efforts of the scientific community and multibillion research investments.…”

Section: Introductionmentioning

confidence: 99%

“…Due to increasing life expectancy in developed countries, AD is a global threat, lacking effective curative or preventive means despite the enormous efforts of the scientific community and multibillion research investments. The key histopathological hallmarks of AD are the accumulation of harmful extracellular amyloid β peptide (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau protein in the hippocampus and neocortex [ 2 , 3 , 4 ]. The Aβ deposition begins 2–3 decades prior to clinical manifestation of AD and precedes the development of tau pathology, which better correlates with the appearance of clinical symptoms [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…The key histopathological hallmarks of AD are the accumulation of harmful extracellular amyloid β peptide (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau protein in the hippocampus and neocortex [ 2 , 3 , 4 ]. The Aβ deposition begins 2–3 decades prior to clinical manifestation of AD and precedes the development of tau pathology, which better correlates with the appearance of clinical symptoms [ 2 , 3 ]. Meanwhile, the definite crosstalk between Aβ and tau protein observed in immunotherapy of AD points out that both these pathways should be targeted in AD therapy [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Meanwhile, the definite crosstalk between Aβ and tau protein observed in immunotherapy of AD points out that both these pathways should be targeted in AD therapy [ 3 ]. Indeed, the anti-Aβ monoclonal antibody aducanumab recently became a first targeted treatment approved by the Food and Drug Administration for AD, whereas two other antibodies targeting Aβ await their accelerated approval [ 2 , 5 ]. Therefore, the anti-Aβ therapy proved to be a viable tactic for the prevention of AD.…”

Section: Introductionmentioning

confidence: 99%

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Ibuprofen Favors Binding of Amyloid-β Peptide to Its Depot, Serum Albumin

Litus

Kazakov

Deryusheva

et al. 2022

IJMS

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The deposition of amyloid-β peptide (Aβ) in the brain is a critical event in the progression of Alzheimer’s disease (AD). This Aβ deposition could be prevented by directed enhancement of Aβ binding to its natural depot, human serum albumin (HSA). Previously, we revealed that specific endogenous ligands of HSA improve its affinity to monomeric Aβ. We show here that an exogenous HSA ligand, ibuprofen (IBU), exerts the analogous effect. Plasmon resonance spectroscopy data evidence that a therapeutic IBU level increases HSA affinity to monomeric Aβ40/Aβ42 by a factor of 3–5. Using thioflavin T fluorescence assay and transmission electron microcopy, we show that IBU favors the suppression of Aβ40 fibrillation by HSA. Molecular docking data indicate partial overlap between the IBU/Aβ40-binding sites of HSA. The revealed enhancement of the HSA–Aβ interaction by IBU and the strengthened inhibition of Aβ fibrillation by HSA in the presence of IBU could contribute to the neuroprotective effects of the latter, previously observed in mouse and human studies of AD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ibuprofen Favors Binding of Amyloid-β Peptide to Its Depot, Serum Albumin

Litus

Kazakov

Deryusheva

et al. 2022

IJMS

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show abstract

“…Alzheimer’s disease (AD) is the leading cause of dementia ( Alzheimer’s Association, 2021 ), affecting around 35 million individuals worldwide hence representing an important strain on health resources ( Cummings et al, 2021 ). However, effective disease-modifying pharmacologic therapies for AD are not currently available ( Tatulian 2022 ). AD is causally related to the accumulation of abnormally folded amyloid-β (Aβ) peptide and hyperphosphorylated tau (pTau) protein aggregates, leading to synapse loss, neurodegeneration, and progressive cognitive decline.…”

Section: Introductionmentioning

confidence: 99%

Amyloid-β Induces Cdh1-Mediated Rock2 Stabilization Causing Neurodegeneration

et al. 2022

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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, which is causally related to the accumulation of abnormally folded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein aggregates. The dendritic spine regulator Rho protein kinase 2 (Rock2) accumulates in the brain at the earliest stages of AD and remains increased during disease progression. However, the molecular mechanism that upregulates Rock2 in AD, and its role in the disease progression, are unknown. Here, we found that oligomers of the amyloidogenic fragment 25–35 of the Aβ peptide (Aβ25-35) trigger Rock2 accumulation and activation in mouse cortical neurons in primary culture and in mouse hippocampus in vivo. Neuronal apoptotic death and memory impairment caused by Aβ25-35 administration were rescued by genetic and pharmacological inhibition of Rock2 activity. Mechanistically, Aβ25-35 elicited cyclin dependent kinase-5 (Cdk5)-mediated phosphorylation of Cdh1, a cofactor that is essential for the activity of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) in neurons. Notably, phosphorylated Cdh1 was disassembled from the APC/C complex, causing its inactivation and subsequent Rock2 protein stabilization and activation. Moreover, Aβ25-35-induced neuronal apoptosis was prevented by expressing a phosphodefective form of Cdh1, but not by a phosphomimetic Cdh1. Finally, Cdh1 inactivation, using both genetic and pharmacological approaches, enhanced Aβ25-35-mediated neuronal death through a mechanism that was prevented by inhibition of Rock2 activity. These results indicate that the Cdk5-Cdh1 signaling pathway accounts for the increased Rock2 activity by amyloidogenic Aβ peptides and that this mechanism may contribute to neurodegeneration and memory loss in AD.

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In vitro and in silico investigation of FDA‐approved drugs to be repurposed against Alzheimer's disease

Akkaya,

Seyhan,

Sari

et al. 2024

Drug Development Research

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Alzheimer's disease (AD), one of the main causes of dementia, is a neurodegenerative disorder. Cholinesterase inhibitors are used in the treatment of AD, but prolonged use of these drugs can lead to serious side effects. Drug repurposing is an approach that aims to reveal the effectiveness of drugs in different diseases beyond their clinical uses. In this work, we investigated in vitro and in silico inhibitory effects of 11 different drugs on cholinesterases. The results showed that trimebutine, theophylline, and levamisole had the highest acetylcholinesterase inhibitory actions among the tested drugs, and these drugs inhibited by 68.70 ± 0.46, 53.25 ± 3.40, and 44.03 ± 1.20%, respectively at 1000 µM. In addition, these drugs are bound to acetylcholinesterase via competitive manner. Molecular modeling predicted good fitness in acetylcholinesterase active site for these drugs and possible central nervous system action for trimebutine. All of these results demonstrated that trimebutine was determined to be the drug with the highest potential for use in AD.

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Challenges and hopes for Alzheimer’s disease

Cited by 163 publications

References 210 publications

Ibuprofen Favors Binding of Amyloid-β Peptide to Its Depot, Serum Albumin

Ibuprofen Favors Binding of Amyloid-β Peptide to Its Depot, Serum Albumin

Amyloid-β Induces Cdh1-Mediated Rock2 Stabilization Causing Neurodegeneration

In vitro and in silico investigation of FDA‐approved drugs to be repurposed against Alzheimer's disease

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