Stable intrachain and interchain complexes of neurofilament peptides: a putative link between Al3+ and Alzheimer disease.

Abstract

The etiologic role ofAl3+ in Alzhelmer disease has been controversial. Circular dichroism (CD) spectrscopic studies on two synthetic Mfrgments of human neurofilament protein mid-sized subunit (NF-M), NF-M13 (KSPVPKSP-VEEKG) and NF-M17 (EEKGKSPVPKSPVEEKG), and their alanine-substituted and/or serine-phosphorylated derivatives were carried out in an attempt to find a molecular mechanm for the effect of A13+ to induce aggregation of neuronal proteins or their catabolic frments. AP+ and Ca2+ ions were found to induce a-pleated sheet formation in the phosphorylated fragments. The cation sensitivity depended on the length and charge distribution ofthe sequence and site ofphosphorylation. Al3+-induced conformational changes were irreversible to citric acid chelation, whereas Ca2+-induced conformational changes were reversible with citric acid. Studies of the alanine derivatives demonstrated which residues affected Al3+ or Ca2+ binding. Peptides containing at least one free (nonphosphorylated) serine residue were shown to form an intramolecular A13+ complex, rather than an intermolecular one. In the intramolecular (intrachain) complex, the ligand function of the deprotonated serine hydroxyl was delineated [(Al'pepH I)-type complex]. Ca2+ ions did not show a tendency for intramolecular complexing. The potential role of Al3+ in Alzhelmer diseae tangle and plaque formation is strongly suggested.Aluminum has been recognized to be a neurotoxic agent, but its etiologic role in Alzheimer disease and other neurodegenerative diseases is still controversial (1-4). There is debate as to whether plaques precede tangles or vice versa. On the basis of a variety of physiological effects of A13+ in culture and animal systems and its consistent occurrence in neurofibrillary tangles (4, 5) and perhaps plaques (4, 6), it has been proposed that aluminum is a major risk factor in many neuronal dysfunctions. Others have questioned the etiologic significance of aluminum, mainly because of the failure of some researchers to find it in amyloid plaques by highly sensitive analytic techniques-i.e., laser microprobe mass analysis (7) and nuclear microscopy (8).There are several ways that enhanced aluminum levels may influence the structural or functional proteinous constituents of nerve cells. The In an attempt to find a molecular mechanism for the effect of aluminum to induce aggregation of neuronal proteins or their catabolic fragments, circular dichroism (CD) spectroscopic studies have been performed in our laboratories on synthetic fragments of human neurofilament mid-sized subunit protein (NF-M), KSPVPKSPVEEKG (NF-M13), and EEKGKSPVPKSPVEEKG (NF-M17), as well as on their alanine-substituted and/or serine-phosphorylated derivatives (15)(16)(17). CD spectra were recorded as described (18) and deconvoluted into secondary structural components by the convex constraint analysis method (19,20 and A13+ were found to induce the adoption of the (3-pleated sheet conformation in the C terminus in a low-dielectricconstant environment, in 2,2,2-...

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