Zinc-Amyloid β Interactions on a Millisecond Time-Scale Stabilize Non-fibrillar Alzheimer-Related Species

Abstract

The role of zinc, an essential element for normal brain function, in the pathology of Alzheimer's disease (AD) is poorly understood. On one hand, physiological and genetic evidence from transgenic mouse models supports its pathogenic role in promoting the deposition of the amyloid beta-protein (Abeta) in senile plaques. On the other hand, levels of extracellular ("free") zinc in the brain, as inferred by the levels of zinc in cerebrospinal fluid, were found to be too low for inducing Abeta aggregation. Remarkably, the release of transient high local concentrations of zinc during rapid synaptic events was reported. The role of such free zinc pulses in promoting Abeta aggregation has never been established. Using a range of time-resolved structural and spectroscopic techniques, we found that zinc, when introduced in millisecond pulses of micromolar concentrations, immediately interacts with Abeta 1-40 and promotes its aggregation. These interactions specifically stabilize non-fibrillar pathogenic related aggregate forms and prevent the formation of Abeta fibrils (more benign species) presumably by interfering with the self-assembly process of Abeta. These in vitro results strongly suggest a significant role for zinc pulses in Abeta pathology. We further propose that by interfering with Abeta self-assembly, which leads to insoluble, non-pathological fibrillar forms, zinc stabilizes transient, harmful amyloid forms. This report argues that zinc represents a class of molecular pathogens that effectively perturb the self-assembly of benign Abeta fibrils, and stabilize harmful non-fibrillar forms.

Zinc ions promote Alzheimer Aβ aggregation via population shift of polymorphic states

“…At certain concentration, increasing zinc not only prevents fibril formation, but also decreases aggregation. This scenario is consistent with experimental observation when mixing rapidly Zn and Aβ (8). In the presence of zinc, the Aβ peptide aggregation rates are always higher than in the Zn 2þ -free solution.…”

“…Oligomerization of the Aβ peptides can be rapidly induced in the presence of Zn 2þ ions under physiological conditions (4, 6, 7). Noy et al (8) have followed Zn 2þ ionenhanced Aβ aggregation. Studies suggested that H6, H13, and H14 at the N-terminal domain of Aβ coordinate with Zn 2þ (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

“…Studies suggested that H6, H13, and H14 at the N-terminal domain of Aβ coordinate with Zn 2þ (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Solution NMR of Zn 2þ -Aβ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] showed that Zn 2þ is bound to these three histidines and E11 (18). A recent NMR study of Zn 2þ -Aβ proposed that Zn 2þ binds to H6, E11, H14, and D1 of rat Aβ 1-28 and to H6, E11, H13, H14, and D1 of human Aβ 1-28 (22).…”

Zn2+-Aβ40 Complexes Form Metastable Quasi-spherical Oligomers That Are Cytotoxic to Cultured Hippocampal Neurons

“…A␤40 Sample Preparation-A␤40 was purchased from rPeptide and prepared for experiments as described previously (14). Briefly, A␤40 was dissolved at 665 M (defined by UV-Vis spectroscopy with ⑀ 292 ϭ 2300 M Ϫ1 cm Ϫ1 ) in 10 mM NaOH, sonicated for 1 min in a Branson 1510 bath sonicator, and centrifuged for 10 min at 12,000 ϫ g at 4°C to precipitate large aggregates.…”

“…Specifically, transgenic mouse models of AD demonstrated significantly reduced loads of cerebral senile plaques and precipitated A␤ when the gene for the synaptic vesicle transporter ZnT3 (SLC30A3) was knocked out (12). In vitro, Zn 2ϩ interacts with A␤40, inducing its aggregation within milliseconds (13,14). It was shown that Zn 2ϩ interacts with soluble A␤40 oligomers and alters their stability (15).…”