Premium
P3‐254: A new approach to tracking progression of molecular pathogenesis in Alzheimer's disease identifies hippocampal iron dyshomeostasis as a novel potential biomarker
Author(s) -
Milward Elizabeth A.,
Ravetti Martin Gomez,
Rosso Osvaldo A.,
Berretta Regina,
Johnstone Daniel,
Moscato Pablo
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1754
Subject(s) - ferritin , ferroportin , gene , biomarker , gene expression , pathogenesis , biology , transcriptome , neurodegeneration , genetics , disease , medicine , biochemistry , immunology , iron homeostasis
Background: Several lines of evidence suggest brain iron accumulation occurs in Alzheimer’s disease. Whether this is accompanied by alterations in expression of iron-related genes is unknown. Methods: Combinatorial optimization methods were used to analyze a published microarray gene expression dataset of hippocampal tissue from 22 AD patients and 9 controls. MaxCover (a,b)-k Feature Set analysis determined gene signatures discriminating controls from ‘‘severe AD’’. Samples classed as ‘‘incipient AD’’ or ‘‘moderate AD’’ using MMSE and NFT scores were assessed based on Jensen-Shannon divergences for divergence from the control signature and convergence to the severe AD signature, providing an alternative estimate of progression of molecular pathogenesis. Results: The 1,372-probe gene expression signature generated by the Feature Set approach included genes relating to iron metabolism. Transcripts for the iron transport proteins lactoferrin and SLC11A1 were higher in many AD cases than controls. Expression of genes encoding the subunits of the iron storage protein ferritin (FTL, FTH1) correlated positively with the degree of divergence of AD brains from controls and with molecular changes consistent with neurodegeneration. Ferric iron taken up into cells must be reduced to ferrous iron before storage in ferritin. The duodenal ferrireductase CYBRD1, which reduces ferric iron in some tissues, likewise correlated positively, although ferriductase activity of CYBRD1 remains to be confirmed in brain. Expression of genes encoding mitochondrial proteins utilizing iron (e.g. ICSA1, ACO2) inversely correlated with disease progression as gauged by convergence to the severe AD signature. There was also altered expression of several genes, notably TPP1 and CLN8, which are causatively linked to the neuronal ceroid lipofuscinoses. These severe and sometimes fatal neurodegenerative genetic diseases are characterized by excessive lipofuscin accumulation in lysosomes, a process thought to be accelerated by iron derived from ferritin degradation. Conclusions: The general increases in ferritin gene expression from incipient through moderate into severe AD suggest disease progression may be accompanied by increased hippocampal iron in ferritin and possibly also in lipofuscin. Since hippocampal iron can now be assessed non-invasively by MRI R2 relaxivity technology, iron dyshomeostasis may provide a new marker for progression of molecular pathogenesis in the AD brain.