International Journal of Molecular Sciences Review The Function of Transthyretin Complexes with Metallothionein in Alzheimer’s Disease Natalia Zar˛ebaand Marta Kepinska * Department of Biomedical and Environmental Analysis, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-71-784-0173 Received: 26 October 2020; Accepted: 24 November 2020; Published: 26 November 2020 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; β-amyloid; metallothionein; protein-protein interaction; transthyretin 1. Introduction Amyloidosis is a disease in which pathological extracellular fibers, being filamentary structures formed by insoluble protein, build up in tissues and organs. Alzheimer’s disease (AD) is one of the local amyloidoses in which amyloid-β peptide (Aβ) is deposited. The disease is characterized by the existence of intracellular neurofibrillary tangles (NFTs) resulting from the accumulation of tau protein associated with microtubules as well as the presence of extracellular senile plaques [1]. These changes occur in the central nervous system (CNS) and, in particular, in the hippocampus and neocortex. Senile plaques are composed of transition metal ions such as Cu2+ or Zn2+ at high concentrations [2] and, mainly, conformationally changed, aggregated, and protease-resistant Aβ [2,3]. The peptide comprises 40 to 43 amino acids and is formed from the amyloid precursor protein (APP) through the proteolytic action of β- and γ-secretase. APP is a transmembrane protein expressed particularly in the CNS [4]. Aβ peptide is able to rise through three different pathways of APP metabolism. The first and principal pathway, namely the non-amyloidogenic pathway (Figure1), assumes cleavage of APP at first by α-secretase between the 612 and 613 amino acids [5]. It leads to the emergence of APPα and a membrane-associated carboxy-terminal fragment (CTF83). Subsequently, γ-secretase forms Aβ17–40/42 peptides or β-secretase generates Aβ1–16 peptide. The other pathway is the amyloidogenic pathway (Figure2). It is less common and involves the cleavage of APP at the beginning by β-secretase, leading to the emergence Int. J. Mol. Sci. 2020, 21, 9003; doi:10.3390/ijms21239003 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 17 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 17 Subsequently, γ-secretase forms Aβ17–40/42 peptides or β-secretase generates Aβ1–16 peptide. The other pathwaySubsequently, is the γamyloidogenic-secretase forms pathway Aβ17–40/42 (Figure peptides 2). or It βis-secretase less common generates and involvesAβ1–16 peptide. the cleavage The other of APPpathway at the is beginning the amyloidogenic by β-secretase, pathway leading (Figure to the 2). emergence It is less common of APPβ andand involvesa membrane-associated the cleavage of Int.APP J. Mol.at the Sci. beginning2020, 21, 9003 by β-secretase, leading to the emergence of APPβ and a membrane-associated2 of 16 carboxy-terminal fragment (CTF99). Subsequently, γ-secretase generates mainly full-length Aβ1–40/42 peptide,carboxy-terminal which could fragment subsequently (CTF99). affect Subsequently, metal ions γin-secretase the brain, generates form soluble mainly oligomers full-length and A fibrils,β1–40/42 andofpeptide, APP thusβ creatingwhichand a membrane-associatedcould senile subsequently plaques (Figure affect carboxy-terminal 2) metal[4,6]. Theions third in fragmentthe pathway brain, (CTF99).form of APP soluble metabolism Subsequently, oligomers that γand-secretase has fibrils, been and thus creating senile plaques (Figure 2) [4,6]. The third pathway of APP metabolism that has been recentlygenerates discovered mainly full-length involves Aηβ-secretase1–40/42 peptide, that cleaves which APP could at subsequently the 504 to 505 affect amino metal acids ions and in generates the brain, Aformrecentlyηα solubleand discovered Aηβ oligomers, which involves andare fibrils,lower η-secretase and molecular thus that creating cleavesmass senile carboxy-terminal APP plaques at the 504 (Figure to 505fragments2) [amino4,6]. The acidsfollowing third and pathway generates second of Aηα and Aηβ, which are lower molecular mass carboxy-terminal fragments following second cleavageAPP metabolism by α- and that β has-secretase, been recently respectively discovered (Figure involves 3) [4,7].η-secretase The first that form cleaves (Aƞα) APP includes at the A 504β1–16 to ƞ 1–16 peptide505cleavage amino in by acidsits αsequence,- andand generates β-secretase, which A isηα often respectivelyand Aregardedηβ, which (Figure as are neurotoxic lower 3) [4,7]. molecular [4]. The Full-length first mass form carboxy-terminal peptides, (A α) includes however, fragments A βare thefollowingpeptide most in abundant secondits sequence, cleavage isoforms which by that αis- often andare β toxicregarded-secretase, to cells as respectivelyneurotoxic and could [4]. (Figurelead Full-length to3 )cellular [ 4,7 ].peptides, Thedeath first [4,6,8].however, form (ATheir ηαare) the most abundant isoforms that are toxic to cells and could lead to cellular death [4,6,8]. Their accumulationincludes Aβ1–16 inpeptide the form in of its aggregates sequence, which indicates is often the regardeddevelopment as neurotoxic of the disease [4]. Full-length [9]. For neuronal peptides, cells,however,accumulation toxic are effects the in mostofthe A formβ abundant can ofalso aggregates be isoforms triggered indicates that by are other toxic the actions, development to cells such and as could ofinternalization the lead disease to cellular [9]. via For pinocytosis, death neuronal [4,6,8]. endocytosisTheircells, accumulationtoxic effects and phagocytosisof in A theβ can form also of[10], be aggregates triggered ion pore indicates by formation, otherthe actions, development and such interaction as internalization of the with disease the [ 9viaserpin-enzyme]. For pinocytosis, neuronal complexcells,endocytosis toxic receptor. effects and ofphagocytosisAβ A canβ can also also be [10],be a receptor triggered ion pore of by advanced formation, other actions, gl ycationand such interaction end as internalizationproducts with and the oxidative viaserpin-enzyme pinocytosis, stress damageendocytosiscomplex [11]. receptor. and phagocytosis Aβ can also [10 be], a ion receptor pore formation, of advanced and gl interactionycation end with products the serpin-enzyme and oxidative complex stress receptor.damage [11]. Aβ can also be a receptor of advanced glycation end products and oxidative stress damage [11]. Figure 1. Schematic diagram illustrating proteolytic cleavage of the APP in the non-amyloidogenic FigureFigure 1.1. SchematicSchematic diagramdiagram illustratingillustrating proteolyticproteolytic cleavagecleavage ofof thethe APPAPP inin thethe non-amyloidogenicnon-amyloidogenic pathway, when APP is cleaved by α- and γ-secretase, respectively, and forms Aβ17–40/42, or when APP pathway,pathway, when when APP APP is is cleaved cleaved by byα α-- and andγ γ-secretase,-secretase, respectively, respectively, and and forms forms A βA17–40β17–40/42/42,, oror whenwhen APPAPP is cleaved by α- and β-secretase and forms Aβ1–16 peptides. Based on [4]. isis cleavedcleaved byby αα-- andand ββ-secretase-secretase andand formsforms AAββ1–161–16 peptides.peptides. Based Based on on [4]. [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 Aβ1–40/42 peptides. This peptide can interact with metal ions from the brain, forming Aβ oligomers and then Aβ fibrils. Based on [4]. Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 17 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 Aβ1–40/42 peptides. This peptide Int. J. Mol. Sci. 2020, 21, 9003 3 of 16 can interact with metal