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[P1–110]: VARIATIONS IN THE AMINO ACIDS SEQUENCE OF AMYLOID‐β: AN OPPORTUNITY TO UNDERSTAND ALZHEIMER's DISEASE
Author(s) -
Atamna Hani
Publication year - 2017
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.2017.06.177
Subject(s) - heme , intracellular , chemistry , biochemistry , amino acid , peptide sequence , hemeprotein , amyloid precursor protein , amyloid (mycology) , stereochemistry , gene , alzheimer's disease , enzyme , disease , medicine , inorganic chemistry , pathology
Background:The amino acids (AA) sequences of Amyloid-b (Ab) peptides in human (hu) and rodent (ro) are identical except for three amino acids, which allows huAb to bind heme tightly but not roAb. Literature search points to that the AA sequence of roAb (i.e., not heme-binding Ab) is shared among species that do not develop Alzheimer Disease (AD) while the AA sequence of huAb (i.e., hemebinding Ab) is shared among species that developADwith age. Our lab is following this lead; however, it is not clear which fraction of the cellular heme may bind with huAb. Regulatory heme (RH) is a unique fraction of total cellular heme that is not committed to a specific protein. RH plays role in intermediary metabolism e.g., in microRNA processing or gene regulations. Methods:We investigated if RH could be the target for huAb in situ. To accomplish this goal, we embarked on developing, for the first time, an assay to specifically measure intracellular RH. Results: We found that the cellular concentration of RH is 4306150nM (about 6% of total heme). Furthermore, the dissociation constant (Kd) of heme from huAb is 140nM, which in conjunction with 430nM intracellular RH, suggest that huAb and RH could tightly complex in situ. Subsequently, we generated evidence that huAb binds and depletes intracellular RH. Despite that roAb and huAb equally form aggregates, only huAb binds RH (roAb’s Kd1⁄41000 nM). The hydrophobic segment that causes Ab to aggregate is identical in both huAb and roAb, while the hydrophilic segment (which binds RH) differs by three amino acids (which bind RH in huAb). Furthermore, huAb-heme complex catalyzes the oxidation of organic molecules using H2O2. Conclusions:The abnormal intermediary metabolism in RH-depleted cells resembles many of the abnormalities of the brain of AD patients. These observations suggest that huAb’s complex with heme may contribute to huAb neurotoxicity.