Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer’s disease?

Pivovarova, O; Höhn, Annika; Grune, Tilman; Pfeiffer, Andreas F. H.; Rudovich, Natalia

doi:10.1080/07853890.2016.1197416

Cited by 98 publications

(78 citation statements)

References 99 publications

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“…A third pathway affected by calpain-1 deletion is the Alzheimer's disease pathway, with significant decrease in IDE and PER2. IDE has been discussed as a potential target for both diabetes and Alzheimer's disease (Pivovarova et al, 2016). The decrease in IDE observed with calpain-1 deletion would suggest that individuals with calpain-1 deletion would show decreased risk for developing AD.…”

Section: Discussionmentioning

confidence: 99%

Deletion of the Capn1 Gene Results in Alterations in Signaling Pathways Related to Alzheimer’s Disease, Protein Quality Control and Synaptic Plasticity in Mouse Brain

Zhou

Wang

et al. 2020

Front. Genet.

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Calpains represent a family of calcium-dependent proteases participating in a multitude of functions under physiological or pathological conditions. Calpain-1 is one of the most studied members of the family, is ubiquitously distributed in organs and tissues, and has been shown to be involved in synaptic plasticity and neuroprotection in mammalian brain. Calpain-1 deletion results in a number of phenotypic alterations. While some of these alterations can be explained by the acute functions of calpain-1, the present study was directed at studying alterations in gene expression that could also account for these phenotypic modifications. RNA-seq analysis identified 354 differentially expressed genes (DEGs) in brain of calpain-1 knock-out mice, as compared to their wild-type strain. Most DEGs were classified in 10 KEGG pathways, with the highest representations in Protein Processing in Endoplasmic Reticulum, MAP kinase and Alzheimer's disease pathways. Most DEGs were down-regulated and validation of a number of these genes indicated a corresponding decreased expression of their encoded proteins. The results indicate that calpain-1 is involved in the regulation of a significant number of genes affecting multiple brain functions. They also indicate that mutations in calpain-1 are likely to be involved in a number of brain disorders.

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Section: Discussionmentioning

confidence: 99%

Deletion of the Capn1 Gene Results in Alterations in Signaling Pathways Related to Alzheimer’s Disease, Protein Quality Control and Synaptic Plasticity in Mouse Brain

Zhou

Wang

et al. 2020

Front. Genet.

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“…Furthermore, the clearance of βA in the brain is associated with an IDE. Therefore, development of IDE activators could be one of the possible drugable target in AD (Matioli & Nitrini, 2015;Pivovarova, Höhn, Grune, Pfeiffer, & Rudovich, 2016;Rom et al, 2019).…”

Section: Insulin-degrading Enzymementioning

confidence: 99%

Natural products and their derivatives as multifunctional ligands against Alzheimer's disease

Patil

Thakur

Sharma

et al. 2019

Drug Development Research

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Alzheimer's disease (AD), a complex neurodegenerative disorder causing multiple cellular changes including impaired cholinergic system, beta‐amyloid (βA) aggregation, tau hyperphosphorylation, metal dyshomeostasis, neuroinflammation, and many other pathways are involved in the pathogenesis of the disease. However, the exact cause of the disease is not known. Natural products such as flavonoids, alkaloids, resveratrol, and curcumin have multifunctional properties, and have drawn the attention of the researchers because these molecules are capable of interacting concurrently with the multiple targets of AD. Therefore, natural products and their derivatives with proven efficacy could be used in the management of the neurodegenerative disorders. This review focuses on the natural product based multitarget directed ligands like tacrine‐coumarin, tacrine‐huperzine A, harmine‐isoxazoline, berberine‐thiophenyl, galantamine‐indole, pyridoxine‐resveratrol, donepezil‐curcumin and their mode of action.

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“…7 Alzheimer's disease is also described as "type 3 diabetes mellitus (DM)." [15][16][17] Brain insulin signalling regulates synaptic plasticity and long-term potentiation. 8 This endogenous impairment can occur in the brain even in the absence of type 2 DM.…”

Section: What Is K Nown and Objec Tivementioning

confidence: 99%

“…9 Insulin signalling has a direct role in controlling NFT, 10 neuroinflammation, 11,12 oxidative stress, 13 activation of various proapoptotic agents 14 and the formation of Aβ plaques. [15][16][17] Brain insulin signalling regulates synaptic plasticity and long-term potentiation. It also maintains the levels of certain neurotransmitters, such as acetylcholine and norepinephrine, that control memory and cognition.…”

Section: What Is K Nown and Objec Tivementioning

confidence: 99%

Scope of new formulation approaches in the repurposing of pioglitazone for the management of Alzheimer’s disease

Jojo

Kuppusamy

2019

J Clin Pharm Ther

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Summary What is known and objective Alzheimer's disease (AD) is the most common cause of dementia among the elderly. The exact cause of the disease is not clearly known, and no existing therapies are able to prevent disease progression. Identification of the possible “impaired brain insulin signalling in AD” enriched the scope for “the repurposing of diabetic drugs in AD management.” Among the different classes of diabetic drugs, pioglitazone (PIO), a PPARγ agonist classed as an insulin sensitizer, is of the highest interest for AD management. The drug is reported to have direct action on multiple targets involved in AD, independent of insulin signalling. Even though PIO has appeared to be a potent molecule in preclinical trials, limited success was observed in the clinical stage. The tentative reasons for the limited therapeutic success in the clinical stage are not clear. The main focus of the review is to discuss various factors that might limit the therapeutic success of PIO in clinical trials and possible approaches to overcome those limitations. Method The research articles, review articles, and patents containing information regarding the clinical and preclinical trials of PIO in AD have been reviewed thoroughly using the keywords related to diabetic drugs in AD, PIO for AD management and mechanism of PIO in AD. Literature search was conducted on PubMed, SCOPUS and EMBASE. Results and discussion Previous studies have indicated that the blood‐brain barrier (BBB) is the biggest challenge to delivering PIO to the brain. Therefore, to attain a therapeutic concentration in the brain, a higher dose is needed, which is also supported by preclinical investigations in AD; however, in clinical studies, scientists have used the usual diabetic doses. This dose is inadequate to attain a therapeutic concentration in the brain and appears to be the primary reason for the limited success of PIO in clinical trials. The stage of drug intervention and the nature of the study population are also influential factors for the therapeutic response. What is new and conclusion The insufficient concentration of the drug reaching the brain appears to be the crucial factor that limits the therapeutic success of PIO in AD management. Since the administration of higher doses cannot be recommended due to safety issues, the current situation demands the use of novel tools to ensure a therapeutic concentration reaches the brain.

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Insulin-degrading enzyme: new therapeutic target for diabetes and Alzheimer’s disease?

Cited by 98 publications

References 99 publications

Deletion of the Capn1 Gene Results in Alterations in Signaling Pathways Related to Alzheimer’s Disease, Protein Quality Control and Synaptic Plasticity in Mouse Brain

Deletion of the Capn1 Gene Results in Alterations in Signaling Pathways Related to Alzheimer’s Disease, Protein Quality Control and Synaptic Plasticity in Mouse Brain

Natural products and their derivatives as multifunctional ligands against Alzheimer's disease

Scope of new formulation approaches in the repurposing of pioglitazone for the management of Alzheimer’s disease

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