Two decades of new drug discovery and development for Alzheimer's disease

Liu, Zhidong; Zhang, Aihua; Sun, Hui; Han, Ying; Kong, Ling; Wang, Xijun

doi:10.1039/c6ra26737h

Cited by 68 publications

(43 citation statements)

References 180 publications

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“…Alzheimer's disease (AD) is a neurodegenerative disorder and one of the most common forms of dementia worldwide (Liu et al, ). Pathologically, it is characterized by the deposition of extracellular amyloid‐β (Aβ) in the brain causing neuronal death in the neocortex and hippocampus, leading to irreversible cognitive impairment and behavioural alterations (Taylor, Hardy, & Fischbeck, ).…”

Section: Introductionmentioning

confidence: 99%

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Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

Cristiano

Volpicelli

Lippiello

et al. 2019

British J Pharmacology

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Background and purpose Alzheimer's disease (AD) is a common neurodegenerative disease characterized by a neuroinflammatory state, and to date, there is no cure and its treatment represents a large unmet clinical need. The involvement of Th17 cells in the pathogenesis of AD‐related neuroinflammation has been reported in several studies. However, the role of the cytokine, IL‐17 has not been well addressed. Herein, we investigate the effects of IL‐17 neutralizing antibody (IL‐17Ab) injected by i.c.v. or intranasal (IN) routes on amyloid‐β (Aβ)‐induced neuroinflammation and memory impairment in mice. Experimental approach Aβ1–42 was injected into cerebral ventricles of adult CD1 mice. These mice received IL‐17Ab via i.c.v. either at 1 h prior to Aβ1–42 injection or IN 5 and 12 days after Aβ1–42 injection. After 7 and 14 days of Aβ1–42 administration, we evaluated olfactory, spatial and working memory and performed biochemical analyses on whole brain and specific brain areas. Key results Pretreatment with IL‐17Ab, given, i.c.v., markedly reduced Aβ1–42‐induced neurodegeneration, improved memory function, and prevented the increase of pro‐inflammatory mediators in a dose‐dependent manner at 7 and 14 days. Similarly, the double IN administration of IL‐17Ab after Aβ1–42 injection reduced neurodegeneration, memory decline, and the levels of proinflammatory mediators and cytokines. Conclusion and implications These findings suggest that the IL‐17Ab reduced neuroinflammation and behavioural symptoms induced by Aβ. The efficacy of IL‐17Ab IN administration in reducing Aβ1–42 neurodegeneration points to a possible future therapeutic approach in patients with AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Section: Introductionmentioning

confidence: 99%

“…Alzheimer's disease (AD) is a neurodegenerative disorder and one of the most common forms of dementia worldwide (Liu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

Cristiano

Volpicelli

Lippiello

et al. 2019

British J Pharmacology

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“…However, small molecule inhibitors or modulators targeting amyloidosis have recently faced several clinical trial challenges. [8,9] Among several compounds, the chemically conserved scaffold molecules characterized by multi aromatic groups have been tested in vitro [10,11] or in vivo. 12 These compounds have been reported to modulate the amyloid aggregation pathways.…”

Section: Introductionmentioning

confidence: 99%

Cationic polymethacrylate-copolymer acts as an agonist for β-amyloid and antagonist for amylin fibrillation

Sahoo

Genjo

Stoddard

et al. 2018

Preprint

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In human, amyloid-beta (A) and islet amyloid polypeptide (hIAPP) aggregations are linked to Alzheimer's disease and Type-2 Diabetes, respectively. There is significant interest in better understanding the aggregation process by using chemical tools. Here, we show the ability of a cationic polymethacrylate-copolymer (PMAQA) to quickly induce -hairpin structure and promote fibrillation in A40, and to constrain the conformational plasticity of hIAPP for several days and inhibit its aggregation at sub-micromolar concentrations. NMR experiments and atomistic molecular dynamics simulations reveal that PMAQA electrostatically interacts with A40's Glu22 and Asp23 followed by β-sheet induction while it binds strongly to the closest proximity of amyloid core domain (NFGAIL) of hIAPP and restrain its structural rearrangement.This study provides a valuable approach to develop polymer-based anti-amyloid inhibitors that may diminish the population of intermediates of A40 or hIAPP.

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“…Alzheimer's disease (AD), has been recognized as one of the most difficult medical problems, with a heavy social and economic cost. 40 The World Alzheimer's Report has estimated there are more than 46 million AD patients worldwide, with an expected increase to 130 million by 2050. [40][41][42] Given that brain pathology precedes clinical symptoms, Kim et al performed MS-based metabolomics to detect whether metabolites in plasma were pathologically related, like cerebrospinal uid (CFS).…”

Section: Metabolomic Analysis For Clinical Biomarker Discoverymentioning

confidence: 99%

Mass spectrometry-based metabolomics in health and medical science: a systematic review

Zhang

et al. 2020

RSC Adv.

132

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Two decades of new drug discovery and development for Alzheimer's disease

Abstract: Alzheimer's disease is a progressive and irreversible neurodegenerative disease, associated with a decreased cognitive function and severe behavioral abnormalities.

Cited by 68 publications

References 180 publications

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

Cationic polymethacrylate-copolymer acts as an agonist for β-amyloid and antagonist for amylin fibrillation

Mass spectrometry-based metabolomics in health and medical science: a systematic review

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