Deferiprone Reduces Amyloid-β and Tau Phosphorylation Levels but not Reactive Oxygen Species Generation in Hippocampus of Rabbits Fed a Cholesterol-Enriched Diet

Abstract

Accumulation of amyloid-β (Aβ) peptide and the hyperphosphorylation of tau protein are major hallmarks of Alzheimer’s disease (AD). The causes of AD are not well known but a number of environmental and dietary factors are suggested to increase the risk of developing AD. Additionally, altered metabolism of iron may have a role in the pathogenesis of AD. We have previously demonstrated that cholesterol-enriched diet causes AD-like pathology with iron deposition in rabbit brain. However, the extent to which chelation of iron protects against this pathology has not been determined. In this study, we administered the iron chelator deferiprone in drinking water to rabbits fed with a 2% cholesterol diet for 12 weeks. We found that deferiprone (both at 10 and 50 mg/kg/day) significantly decreased levels of Aβ40 and Aβ42 as well as BACE1, the enzyme that initiates cleavage of amyloid-β protein precursor to yield Aβ. Deferiprone also reduced the cholesterol diet-induced increase in phosphorylation of tau but failed to reduce reactive oxygen species generation. While deferiprone treatment was not associated with any change in brain iron levels, it was associated with a significant reduction in plasma iron and cholesterol levels. These results demonstrate that deferiprone confers important protection against hypercholesterolemia-induced AD pathology but the mechanism(s) may involve reduction in plasma iron and cholesterol levels rather than chelation of brain iron. We propose that adding an antioxidant therapy to deferiprone may be necessary to fully protect against cholesterol-enriched diet-induced AD-like pathology.

Treating Alzheimer's disease by targeting iron

“…In animal models of Parkinson's disease, it has been shown to improve motor performance (Aguirre et al, ; Ayton, Lei, Duce, et al, ; Ayton, Lei, et al, ; Devos et al, ; Dexter et al, ; Workman et al, ). Deferiprone is neuroprotective in neuronal culture models of Aβ toxicity (Molina‐Holgado, Gaeta, Francis, Williams, & Hider, ; Part et al, ), and it has been shown to reduce Aβ burden and tau phosphorylation in a rabbit model of AD (Prasanthi et al, ). Deferiprone was shown to lower brain iron levels (as assessed by MRI and CSF ferritin) and improve motor performance in a Phase 2 study of Parkinson's disease (Devos et al, ), and there is now a Phase 2 study underway for AD (clinicaltrials.gov identifier: NCT03234686).…”

“…In animal models of Parkinson's disease, it has been shown to improve motor performance (Aguirre et al, 2015;Ayton, Lei, Duce, et al, 2013;Ayton, Lei, et al, 2015;Devos et al, 2014;Dexter et al, 2011;Workman et al, 2015). Deferiprone is neuroprotective in neuronal culture models of Aβ toxicity (Molina-Holgado, Gaeta, Francis, Williams, & Hider, 2008;Part et al, 2015), and it has been shown to reduce Aβ burden and tau phosphorylation in a rabbit model of AD (Prasanthi et al, 2012).…”

Vitamin E, Turmeric and Saffron in Treatment of Alzheimer’s Disease

“…The scientists suggested that cholesterol-enriched diet may increase body iron deposition that may lead AD. Administering various metal chelators that will help prevent free radical reactions could be helpful in treating the disease [8,121,122]. Curcumin was found to have a high binding affinity for iron and copper, that may work as an iron chelator in AD [123,124].…”

“…Although the pathogenesis of the disease is still not fully understood there is a growing consensus that behind the complex molecular mechanism appears to be the accumulation and aggregation of protein fragments. Amyloid-Beta (Aβ), known as amyloid plaques on the blood vessels and the accumulation of intracellular neurofibrillary tangles (tau) that block neurotransmitters and alter metabolism of iron, cause the destruction of nerve cells that accompanies Alzheimer’s [5,6,7,8,9,10,11,12]. It is reported that increased Aβ levels in AD patients reduce plasmalogen levels [13], increase the formation of reactive oxidative species, and slowly obstruct cerebral function [14,15].…”

Advance of sporadic Alzheimer's disease animal models

“…High cholesterol diet‐induced AD animal model can be applied to study the relationship between lipid metabolism disorders and AD pathological progress. However, the pathology of hyperphosphorylated Tau protein seldom occurred in the animal models fed with a high‐cholesterol high‐fat diet . The reason for the difference might be that the animals with inappropriate age have been employed in this model.…”