STABLE INTRACHAIN AND INTERCHAIN COMPLEXES OF NEUROFILAMENT PEPTIDES - A PUTATIVE LINK BETWEEN AL3-DISEASE( AND ALZHEIMER)

The etiologic role of Al3+ in Alzheimer disease has been controversial . Circular dichroism (CD) spectroscopic studies on two synthetic fragm ents of human neurofilament protein mid-sized subunit (NF-M), NF-M13 ( KSPVPKSPVEEKG) and NF-M17 (EEKGKSPVPKSPVEEKG), and their alanine-subst ituted and/or serine-phosphorylated derivatives were carried out in an attempt to find a molecular mechanism for the effect of Al3+ to induc e aggregation of neuronal proteins or their catabolic fragments. Al3and Ca2+ ions were found to induce beta-pleated sheet formation in the phosphorylated fragments. The cation sensitivity depended on the leng th and charge distribution of the sequence and site of phosphorylation . Al3+-induced conformational changes were irreversible to citric acid chelation, whereas Ca2+-induced conformational changes were reversibl e with citric acid. Studies of the alanine derivatives demonstrated wh ich residues affected Al3+ or Ca2+ binding. Peptides containing at lea st one free (nonphosphorylated) serine residue were shown to form an i ntramolecular Al3+ complex, rather than an intermolecular one. In the intramolecular (intrachain) complex, the ligand function of the deprot onated serine hydroxyl was delineated [(Al.pepH(-1))-type complex]. Ca 2+ ions did not show a tendency for intramolecular complexing. The pot ential role of Al3+ in Alzheimer disease tangle and plaque formation i s strongly suggested.