The Oral Iron Chelator, Deferasirox, Reverses the Age-Dependent Alterations in Iron and Amyloid-β Homeostasis in Rat Brain: Implications in the Therapy of Alzheimer's Disease.
The altered metabolism of iron impacts the brain function in multiple deleterious ways during normal aging as well as in Alzheimer's disease. We have shown in this study that chelatable iron accumulates in the aged rat brain along with overexpression of transferrin receptor 1 (TfR1) and ferritin, accompanied by significant alterations in amyloid-β (Aβ) peptide homeostasis in the aging brain, such as an increased production of the amyloid-β protein precursor, a decreased level of neprilysin, and increased accumulation of Aβ42. When aged rats are given daily the iron chelator, deferasirox, over a period of more than 4 months starting from the 18th month, the age-related accumulation of iron and overexpression of TfR1 and ferritin in the brain are significantly prevented. More interestingly, the chelator treatment also considerably reverses the altered Aβ peptide metabolism in the aging brain implying a significant role of iron in the latter phenomenon. Further, other results indicate that iron accumulation results in oxidative stress and the activation of NF-κB in the aged rat brain, which are also reversed by the deferasirox treatment. The analysis of the results together suggests that iron accumulation and oxidative stress interact at multiple levels that include transcriptional and post-transcriptional mechanisms to bring about changes in the expression levels of TfR1 and ferritin and also alterations in Aβ peptide metabolism in the aging rat brain. The efficacy of deferasirox in preventing age-related changes in iron and Aβ peptide metabolism in the aging brain, as shown here, has obvious therapeutic implications for Alzheimer's disease.
Department of Biochemistry, Institute of Post Graduate Medical and Educational Research, Kolkata, India.
Priyanjalee
P
Banerjee
Department of Biochemistry, Institute of Post Graduate Medical and Educational Research, Kolkata, India.
Arghyadip
A
Sahoo
Department of Biochemistry, Institute of Post Graduate Medical and Educational Research, Kolkata, India.
Shruti
S
Anand
Department of Biochemistry, ICARE Institute of Medical Sciences and Research, Haldia, India.
Aritri
A
Bir
Department of Biochemistry, ICARE Institute of Medical Sciences and Research, Haldia, India.
Sasanka
S
Chakrabarti
D000284:Administration, Oral; D000375:Aging / Q000187:drug effects*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000077588:Deferasirox; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D015260:Neprilysin / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism*; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D013053:Spectrophotometry; D014230:Triazoles / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001565:Benzoates; D007502:Iron Chelating Agents; D016328:NF-kappa B; D010446:Peptide Fragments; D011990:Receptors, Transferrin; C545564:Tfrc protein, rat; D014230:Triazoles; C075222:amyloid beta-protein (1-42); D005293:Ferritins; D007501:Iron; D053829:Amyloid Precursor Protein Secretases; D015260:Neprilysin; D000077588:Deferasirox
Alzheimer’s disease; amyloid-β 42; brain aging; ferritin; iron; oxidative stress; transferrin receptor