Metal Ion Effects on Aβ and Tau Aggregation

Abstract

Amyloid and tau aggregation are implicated in manifold neurodegenerative diseases and serve as two signature pathological hallmarks in Alzheimer’s disease (AD). Though aging is considered as a prominent risk factor for AD pathogenesis, substantial evidence suggests that an imbalance of essential biometal ions in the body and exposure to certain metal ions in the environment can potentially induce alterations to AD pathology. Despite their physiological importance in various intracellular processes, biometal ions, when present in excessive or deficient amounts, can serve as a mediating factor for neurotoxicity. Recent studies have also demonstrated the contribution of metal ions found in the environment on mediating AD pathogenesis. In this regard, the neuropathological features associated with biometal ion dyshomeostasis and environmental metal ion exposure have prompted widespread interest by multiple research groups. In this review, we discuss and elaborate on findings from previous studies detailing the possible role of both endogenous and exogenous metal ions specifically on amyloid and tau pathology in AD.

Copper(II) Coordination Abilities of the Tau Protein's N‐Terminus Peptide Fragments: A Combined Potentiometric, Spectroscopic and Mass Spectrometric Study

“…Both thermodynamic and spectral data reveal a good agreement in the complex formation processes of Tau (9)(10)(11)(12)(13)(14)(15)(16) and other terminally protected peptides containing one internal histidyl residue, e. g. the various peptide fragments of prion protein outside the octarepeat domain. [20,22] According to the spectral data, the first two species ([CuHL] and [CuL] À ) correspond to the coordination of the imidazole side chain but the equilibrium constant calculated for the CuÀ N im binding is slightly higher than the values obtained for the various prion fragments. The stability constants for a simple imidazole coordination is generally around log K = 4.0 � 0.2.…”

“…[21] These previous studies strongly support the involvement of metal ions in the formation of neurofibrillary tangles but the exact characterization of the metal binding sites has not been satisfactorily clarified. [8,22] Imidazole-N donors of histidine are effective metal binding sites of proteins [23,24] and tau protein is relatively rich in this residue. Tau protein sequence also shows some methionine residues especially in the N-terminal domain.…”

Zinc Induces Temperature-Dependent Reversible Self-Assembly of Tau

“…PHF remains the most studied form of Tau aggregates. Among the endogenous factors that have been shown or suggested to favor Tau aggregation are post-transitional modifications (in particularly hyper-phosphorylation), mutations and the presence of zinc ions [13][14][15][16]. Interestingly, zinc ions were found to play a critical role in the development of several different NDs including AD and PD.…”

Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

“…And it is widely believed that brain iron dyshomeostasis is closely associated with the formation of NFTs and the progression of tau-mediated neurodegeneration. Iron not only can regulate tau phosphorylation but also can induce the aggregation of hyperphosphorylated tau (Kim et al, 2018;Rao and Adlard, 2018). Indeed, iron deposition is colocalized with NFTs in a special brain region associated with the progression of neurodegeneration (Rao and Adlard, 2018).…”

“…Furthermore, many proline-directed protein kinases are also closely interrelated with tau phosphorylation in AD such as glycogen synthase kinase-3 (GSK3), cyclin-dependent protein kinase-5 (CDK5), and mitogen-activated protein kinases (MAPKs) (Jouanne et al, 2017). Indeed, excess neuronal iron can promote tau hyperphosphorylation and facilitate the formation of NFTs through cyclin-dependent kinase (CDK5)/P25 complex and GSK-3β kinase pathways (Guo et al, 2013;Vossel et al, 2015;Kim et al, 2018;. Additionally, the study also shows that dysfunctional insulin signaling is associated with iron-induced abnormal phosphorylation of tau in AD (Wan et al, 2019).…”