Curcumin and Novel Synthetic Analogs in Cell-Based Studies of Alzheimer's Disease.

Stella Gagliardi,Stefano Sorrentino,Alfredo Costa,John R Cashman,Stefano Bernuzzi,Cristina Cereda,Orietta Pansarasa,Cecilia Pandini,Paola Rota,Elena Sinforiani,Susanna Zucca,Valentina Franco

doi:10.3389/fphar.2018.01404

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is associated with the most common type of dementia and is characterized by the presence of deposits of the protein fragment amyloid beta (Aβ) in the brain. The natural product mixture of curcuminoids that improves certain defects in innate immune cells of AD patients may selectively enhance Aβ phagocytosis by alteration of gene transcription. In this work, we evaluated the protective effects of curcuminoids in cells from AD patients by investigating the effect on NF-κB and BACE1 signaling pathways. These results were compared to the gene expression profile of the clearance of Aβ. The minor curcumin constituent, bisdemethoxycurcumin (BDC) showed the most potent protective action to decrease levels of NF-κB and BACE1, decrease the inflammatory cascade and diminish Aβ aggregates in cells from AD patients. Moreover, mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3) and vitamin D receptor (VDR) gene mRNAs were up-regulated in peripheral blood mononuclear cells from AD patients treated with BDC. BDC treatment impacts both gene expression including Mannosyl (Beta-1,4-)-Glycoprotein Beta-1,4-N-Acetylglucosaminyltransferase, Vitamin D and Toll like receptor mRNA and Aβ phagocytosis. The observation of down-regulation of BACE1 and NF-κB following administration of BDC to cells from AD patients as a model system may have utility in the treatment of asymptomatic AD patients.

Highlights

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that represents the most common type of dementia
High-Performance Liquid Chromatography (HPLC) analysis conducted on peripheral blood mononuclear cells (PBMCs) samples from AD patients and healthy volunteers treated with curcuminoids (i.e., 10 μM for 24 h) showed the presence of compounds in the cellular pellet
Curcumins were absent in the supernatant of cells from both AD patients and healthy subjects treated with curcumins (Figures 4A,C)

Summary

Introduction

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that represents the most common type of dementia. The disproportionate accumulation and aberrant aggregation of Aβ is associated with the onset of neurodegenerative processes. Medications available to treat AD address symptomatic issues and target glutamatergic and cholinergic neurotransmissions and often show only modest clinical benefits (Kumar et al, 2015). Recent achievements in clinical trials of novel diseasemodifying drugs such as aducanumab, show that targeting Aβ clearance represents a promising strategy in prevention and treatment of AD (Panza et al, 2016). Aducanumab decreased Aβ accumulation and slows cognitive decline in subjects during early stages of AD or in mild cognitive impairment patients (Panza et al, 2016).

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