Alzheimer's disease failed clinical trials

Asher, Shreya; Priefer, Ronny

doi:10.1016/j.lfs.2022.120861

Cited by 52 publications

(36 citation statements)

References 58 publications

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“…Increasing evidence indicates that AD is a complex neurodegenerative disease. Although most clinical trials have failed for a multitude of reasons, the understanding of the underlying molecular mechanisms of AD is still in its infancy because of the complexity of its pathophysiology ( Asher and Priefer, 2022 ; Qiu, 2022 ; Therriault et al, 2022 ; Uwishema et al, 2022 ). More specific biomarkers or therapeutic targets that can accelerate the efforts to improve and simplify the areas of differential diagnosis and understand the molecular basis of AD are urgently needed ( Koníčková et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Nucleosome assembly protein 1-like 5 alleviates Alzheimer’s disease-like pathological characteristics in a cell model

Wang

Liu

Sun

2022

Front. Mol. Neurosci.

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Alzheimer’s disease (AD) remains one of the most common dementias of neurodegenerative disease-related diseases. Nucleosome assembly protein 1-like 5 (NAP1L5) belongs to the NAP1L protein family, which acts as a histone chaperone. However, the function and mechanism of NAP1L5 in AD are still unclear. Bioinformatics analysis, RT-qPCR, and Western blotting results showed that NAP1L5 was downregulated in the brain tissues of AD patients and a mouse cell model of AD. NAP1L5 overexpression alleviated (Amyloid-β precursor protein) APP metabolism and Tau phosphorylation. We further demonstrated that NAP1L5 regulated the AD-like pathological characteristics through the GSK3B/Wnt/β-Catenin signaling pathway. Moreover, we showed that the Wnt/β-Catenin signaling pathway, regulated by NAP1L5, was mediated by AQP1-mediated mechanism in N2a-APP695sw cell. In sum, these results suggested that NAP1L5 overexpression has neuroprotective effects and might act as potential biomarker and target for the diagnosis and treatment of AD.

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Section: Discussionmentioning

confidence: 99%

Nucleosome assembly protein 1-like 5 alleviates Alzheimer’s disease-like pathological characteristics in a cell model

Wang

Liu

Sun

2022

Front. Mol. Neurosci.

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“…Because the pathogenesis of AD is complex and involves multiple pathways, combination drug therapy or multitarget drugs have the potential to impact the progression of AD significantly more than a single drug with only one target [ 36 ]. Selecting an appropriate single target to hit is an extremely difficult task, as suggested by the high number of clinical failures when testing single-target disease-modifying drugs for AD [ 35 , 36 ]. Among the multiple mechanisms that influence the progression of AD, such as accumulation of Aβ, chronic neuroinflammation, vascular dysfunction, formation of tau tangles, and neurodegeneration, neuroinflammation and neurodegeneration are particularly important [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, S100A9 has intrinsic amyloidogenic properties, similar to those of Aβ, leading to oligomers, fibrils, and plaque formation, and has the ability to co-aggregate with Aβ, which further enhances neuroinflammation [ 25 , 28 , 29 ]. Neutralizing each of these targets (Aβ, RAGE, S100A9, and TLR4) individually has been shown to slow cognitive decline in animal models [ 30 , 31 , 32 , 33 , 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

Selecting Multitarget Peptides for Alzheimer’s Disease

et al. 2022

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Alzheimer’s disease (AD) is a multifactorial disease with a complex pathogenesis. Developing multitarget drugs could be a powerful strategy to impact the progressive loss of cognitive functions in this disease. The purpose of this study is to select a multitarget lead peptide candidate among a series of peptide variants derived from the neutrophil granule protein cathepsin G. We screened eight peptide candidates using the following criteria: (1) Inhibition and reversion of amyloid beta (Aβ) oligomers, quantified using an enzyme-linked immunosorbent assay (ELISA); (2) direct binding of peptide candidates to the human receptor for advanced glycation end-products (RAGE), the Toll-like receptor 4 (TLR4) and the S100 calcium-binding protein A9 (S100A9), quantified by ELISA; (3) protection against Aβ oligomer-induced neuronal cell death, using trypan blue to measure cell death in a murine neuronal cell line; (4) inhibition of TLR4 activation by S100A9, using a human TLR4 reporter cell line. We selected a 27-mer lead peptide that fulfilled these four criteria. This lead peptide is a privileged structure that displays inherent multitarget activity. This peptide is expected to significantly impact cognitive decline in mouse models of Alzheimer’s disease, by targeting both neuroinflammation and neurodegeneration.

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“…The tau-hyperphosphorylated protein and beta-amyloid (specifically the variant Aβ42) are proteins produced by the brain, the latter of which the brain is unable to eliminate. Both of these proteins then accumulate and start damaging neurons (the cells of our brain) many years before memory disturbances appear [ 68 , 69 ]. Cell death begins in a region of the brain called the hippocampus.…”

Section: Neuroprotective Effect Of Caffeine In Neuroinflammatory and ...mentioning

confidence: 99%

Neurodegenerative Diseases: Can Caffeine Be a Powerful Ally to Weaken Neuroinflammation?

Ruggiero

Calvello

Porro

et al. 2022

IJMS

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In recent years, there has been considerable research showing that coffee consumption seems to be beneficial to human health, as it contains a mixture of different bioactive compounds such as chlorogenic acids, caffeic acid, alkaloids, diterpenes and polyphenols. Neurodegenerative diseases (NDs) are debilitating, and non-curable diseases associated with impaired central, peripheral and muscle nervous systems. Several studies demonstrate that neuroinflammation mediated by glial cells—such as microglia and astrocytes—is a critical factor contributing to neurodegeneration that causes the dysfunction of brain homeostasis, resulting in a progressive loss of structure, function, and number of neuronal cells. This happens over time and leads to brain damage and physical impairment. The most known chronic NDs are represented by Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). According to epidemiological studies, regular coffee consumption is associated with a lower risk of neurodegenerative diseases. In this review, we summarize the latest research about the potential effects of caffeine in neurodegenerative disorders prevention and discuss the role of controlled caffeine delivery systems in maintaining high plasma caffeine concentrations for an extended time.

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Alzheimer's disease failed clinical trials

Cited by 52 publications

References 58 publications

Nucleosome assembly protein 1-like 5 alleviates Alzheimer’s disease-like pathological characteristics in a cell model

Nucleosome assembly protein 1-like 5 alleviates Alzheimer’s disease-like pathological characteristics in a cell model

Selecting Multitarget Peptides for Alzheimer’s Disease

Neurodegenerative Diseases: Can Caffeine Be a Powerful Ally to Weaken Neuroinflammation?

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