A New Perspective of Lysosomal Cation Channel-Dependent Homeostasis in Alzheimer’s Disease

Ezeani, Martin; Omabe, Maxwell

doi:10.1007/s12035-015-9108-3

Cited by 13 publications

(7 citation statements)

References 53 publications

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“…Peroxidized lipids can generate toxic products such as 4-hydroxy-2-nonenal (HNE) and 2-propenal (acrolein) that migrate to different parts of neurons and cause multiple harmful alterations to cellular activity. The deleterious functions associated with neuronal death include the inhibition of ion-motive ATPases and glial cell Na + -dependent glutamate transport, loss of Ca 2+ homoeostasis, and disruption of signaling pathways [201][202][203] . In addition to proteins and lipids, oxidative stress induced by Aβ aggregation has also been reported to cause DNA oxidation, leading to DNA damage.…”

Section: Aβ Forms and Their Toxicitymentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

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Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β-and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β-and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

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Section: Aβ Forms and Their Toxicitymentioning

confidence: 99%

Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

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“…The different gating and ion conducting properties of TPC1 and TPC2 suggest that these two ion channels may play complementary physiological roles as calcium release channels of the endolysosomal system [42]. In accordance with the presence of Aβ42 and tau proteins found along clathrin endolysosomal internalization pathway, a mechanism based on abnormal lysosomal pH and TPC2dependent cation homeostasis in Alzheimer's disease has been suggested [43]. Similar disruptions in lysosomal Ca 2+ signaling might exist in Parkinson disease [44].…”

Section: Wo/2018/086530mentioning

confidence: 94%

Patent Highlights April–May 2018

Mucke¹

2018

Pharm. Pat. Anal.

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Inflammatory bowel diseases seem to be triggered by an intestinal epithelial dysfunction, probably in response to danger signals that might only suggest the presence of pathogens but nevertheless amplify and sustain the release of proinflammatory cytokines. There is considerable evidence that activation of purinergic receptors by nucleotides such as ATP and UTP, constitutes at least part of these signals and not only in the intestinal tract [1,2]. This signaling is terminated by nucleoside triphosphate diphosphohydrolases (e.g., NTPDase-1, CD39). NTPDases are expressed by immunosuppressive supTh17 T-helper cells [3]. The inventors have demonstrated that NTPDase-8 is expressed on epithelial cells at the apical surface of the mouse and human colon. Although its gross effect on nucleotide hydrolysis in the entire intestine is minimal, its precise localization makes it a most important regulator of intestinal inflammation. Degradation of nucleotides by apyrase, selective blockade of P2Y6 receptors by MRS 2578 or knockout of the P2Y2 receptor protects mice against dextran sodium sulfate-induced colitis and decreases epithelial permeability and chemokine secretion. Selective P2Y2 and P2Y6 ligands have been described [4] but antagonists are rare.

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“…Moreover, the formation of aggregates leads to the generation of free radicals as reactive oxygen species (ROS), which are the cause of the formation of oxidized proteins and peroxided lipids. These, in turn, bring about a number of unfavorable changes in cellular activity, including: ion-motive ATPases dysfunction, impaired function of glucose and glutamate transporters, Ca 2+ homeostasis disorders, dysfunction of various signaling pathways and even DNA oxidation [ 35 , 36 , 37 ]. Additionally, increased concentration and aggregation of Aβ stimulates the response of the innate immune system: it activates phagocytosis and immune receptors.…”

Section: Pathophysiology Of Alzheimer’s Diseasementioning

confidence: 99%

Activity of Selected Group of Monoterpenes in Alzheimer’s Disease Symptoms in Experimental Model Studies—A Non-Systematic Review

Wojtunik-Kulesza

Rudkowska

Kasprzak-Drozd

et al. 2021

IJMS

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Alzheimer’s disease (AD) is the leading cause of dementia and cognitive function impairment. The multi-faced character of AD requires new drug solutions based on substances that incorporate a wide range of activities. Antioxidants, AChE/BChE inhibitors, BACE1, or anti-amyloid platelet aggregation substances are most desirable because they improve cognition with minimal side effects. Plant secondary metabolites, used in traditional medicine and pharmacy, are promising. Among these are the monoterpenes—low-molecular compounds with anti-inflammatory, antioxidant, enzyme inhibitory, analgesic, sedative, as well as other biological properties. The presented review focuses on the pathophysiology of AD and a selected group of anti-neurodegenerative monoterpenes and monoterpenoids for which possible mechanisms of action have been explained. The main body of the article focuses on monoterpenes that have shown improved memory and learning, anxiolytic and sleep-regulating effects as determined by in vitro and in silico tests—followed by validation in in vivo models.

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A New Perspective of Lysosomal Cation Channel-Dependent Homeostasis in Alzheimer’s Disease

Cited by 13 publications

References 53 publications

Amyloid beta: structure, biology and structure-based therapeutic development

Amyloid beta: structure, biology and structure-based therapeutic development

Patent Highlights April–May 2018

Activity of Selected Group of Monoterpenes in Alzheimer’s Disease Symptoms in Experimental Model Studies—A Non-Systematic Review

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