The Function of Transthyretin Complexes with Metallothionein in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is one of the most frequently diagnosed types of dementia in the elderly. An important pathological feature in AD is the aggregation and deposition of the β-amyloid (Aβ) in extracellular plaques. Transthyretin (TTR) can cleave Aβ, resulting in the formation of short peptides with less activity of amyloid plaques formation, as well as being able to degrade Aβ peptides that have already been aggregated. In the presence of TTR, Aβ aggregation decreases and toxicity of Aβ is abolished. This may prevent amyloidosis but the malfunction of this process leads to the development of AD. In the context of Aβplaque formation in AD, we discuss metallothionein (MT) interaction with TTR, the effects of which depend on the type of MT isoform. In the brains of patients with AD, the loss of MT-3 occurs. On the contrary, MT-1/2 level has been consistently reported to be increased. Through interaction with TTR, MT-2 reduces the ability of TTR to bind to Aβ, while MT-3 causes the opposite effect. It increases TTR-Aβ binding, providing inhibition of Aβ aggregation. The protective effect, assigned to MT-3 against the deposition of Aβ, relies also on this mechanism. Additionally, both Zn₇MT-2 and Zn₇MT-3, decrease Aβ neurotoxicity in cultured cortical neurons probably because of a metal swap between Zn₇MT and Cu(II)Aβ. Understanding the molecular mechanism of metals transfer between MT and other proteins as well as cognition of the significance of TTR interaction with different MT isoforms can help in AD treatment and prevention.

Keywords: Alzheimer’s disease; metallothionein; protein-protein interaction; transthyretin; β-amyloid.

Figure 1

Schematic diagram illustrating proteolytic cleavage of the APP in the non-amyloidogenic pathway, when APP is cleaved by α- and γ-secretase, respectively, and forms Aβ_17–40/42, or when APP is cleaved by α- and β-secretase and forms Aβ_1–16 peptides. Based on [4].

Figure 2

Schematic diagram illustrating cleavage of APP in the amyloidogenic pathway, when APP is cleaved by β- and γ-secretase, respectively, and forms full-length Aβ_1–40/42 peptides. This peptide can interact with metal ions from the brain, forming Aβ oligomers and then Aβ fibrils. Based on [4].

Figure 3

Schematic diagram illustrating proteolytic cleavage of APP in the ƞ-secretase pathway, when APP is cleaved by ƞ-secretase and then by α- and β-secretase, respectively, and forms Aƞα and Aƞβ peptides accordingly.

Figure 4

A schematic effect of different MT isoforms on TTR ability of Aβ binding: (a) MT-2 reduces binding interaction between TTR and Aβ so the removal of Aβ will be less efficient while (b) MT-3 increases the ability of TTR to bind Aβ, producing the opposite effect to MT-2.