Alzheimer's disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions.

https://www.mdpi.com/1420-3049/25/10/2439/pdf

The Positive Side of the Alzheimer's Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1.

Transthyretin (TTR), a homotetrameric protein that transports thyroxine and retinol both in plasma and in cerebrospinal (CSF) fluid provides a natural protective response against Alzheimer’s disease (AD), modulates amyloid-β (Aβ) deposition by direct interaction and co-localizes with Aβ in plaques. TTR levels are lower in the CSF of AD patients. Zn2+, Mn2+ and Fe2+ transform TTR into a protease able to cleave Aβ. To explain these activities, monomer dissociation or conformational changes have been suggested. Here, we report that when TTR crystals are exposed to copper or iron salts, the tetramer undergoes a significant conformational change that alters the dimer-dimer interface and rearranges residues implicated in TTR’s ability to neutralize Aβ. We also describe the conformational changes in TTR upon the binding of the various metal ions. Furthermore, using bio-layer interferometry (BLI) with immobilized Aβ(1–28), we observe the binding of TTR only in the presence of copper. Such Cu2+-dependent binding suggests a recognition mechanism whereby Cu2+ modulates both the TTR conformation, induces a complementary Aβ structure and may participate in the interaction. Cu2+-soaked TTR crystals show a conformation different from that induced by Fe2+, and intriguingly, TTR crystals grown in presence of Aβ(1–28) show different positions for the copper sites from those grown its absence.

/pdf/copper-mediated-amyloid-b-binding-to-transthyretin-ur93gecrko.pdf

Copper mediated amyloid-β binding to Transthyretin.

Human TTR conformation altered by rhenium tris-carbonyl derivatives.

Amyloid is a term used to describe a set of diseases caused by protein misfolding. There are 36 proteins known to undergo amyloidosis to date. They each unfold from their unique native states and refold into a specific cross β- sheet motif to which various macromolecules can bind. These protein deposits invade tissues and organs disrupting tissue structure and function. The protein serum amyloid P (SAP) is a universal component to all amyloid deposits regardless of the protein involved. It is a disc shaped protein which is known to protect amyloid fibres against degradation. The role of SAP in amyloidosis has been a subject of discussion for many years. Some have found SAP to enhance fibre formation whereas others have found SAP to prevent it. This thesis can be divided into two parts. The first half focuses on the molecular analysis of SAP in relation to amyloid fibre growth whereas the second half focuses solely on the structural aspects of SAP. Chapters 2 and 3 demonstrate that SAP actually exhibits a dual role in relation to fibrillogenesis. It is capable of acting as both a chaperone and a fibrillogenic enhancer depending on its conformation at the time. As a monomer SAP is responsible for the enhancement and stabilisation of fibres whereas in its dimerised form it demonstrates characteristics similar to that of a molecular chaperone. Recent developments in amyloid treatment involve the removal of SAP from deposits using anti-SAP antibodies. As of yet, structural analysis has not been carried out on the SAP:antibody complex. Chapters 4 and 5 conclude this thesis by using crystallographic techniques to demonstrate that a single antibody binds to an SAP molecule during dissociation from amyloid deposits.

The role of serum amyloid P in amyloidosis

Amyloidosis refers to the extracellular deposition of fibrils that are composed of low molecular weight subunits of a variety of serum proteins. The most common familial amyloidosis is caused by the transthyretin protein. People who are born with inherited mutations in the transthyretin gene produce abnormal, (“variant”) transthyretin throughout their liver. The clinical manifestations vary, depending upon the particular substitution, but result either in neuropathy, cardiomyopathy, or both. One of the most common hereditary transthyretin amyloid cardiomyopathies is caused by the Val122IIe mutation. Progressive amyloid deposition in the myocardium and/or in the electrical conduction system is responsible for restrictive cardiomyopathy and unpredictable episodes of arrhythmias and/or severe conduction disorders. The vast majority of transthyretin-familial amyloidotic polyneuropathy cases are associated with Val30Met mutation. The main neuropathic feature of transthyretin amyiloidosis is a progressive sensorimotor and autonomic neuropathy. The first step in evaluating a patient with transthyretin amyloidosis consists in establishing the diagnosis and then evaluating the extent of disease. Deposition of amyloid via tissue can be demonstrated by Congo red staining of biopsy specimens. In all cases, amyloid typing has to be completed by transthyretin gene sequencing and by immunofixation electrophoresis of serum and urine. Current treatment options for patients with transthyretin amyiloidosis are limited. For patients with transthyretin-primary familial amyloidosis who have mild or moderate disease and a diagnosis confirmed by genetic testing and biopsy, liver transplant is the current standard of care.

Mihaela Laszlo

Papers

Transthyretin amyloidosis: an over review