Current and future treatment of amyloid diseases

Abstract

There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross-β-sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid β-peptide (Aβ) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit Aβ formation and aggregation or to enhance Aβ clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent Aβ aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment.

Keywords: Alzheimer's disease; amyloidosis; transthyretin; treatment; type 2 diabetes.

Fig. 1

BRICHOS inhibition of Aβ fibril formation. BRICHOS binds to the surface of the Aβ fibril where it specifically protects the sites at which secondary nucleation events take place, thereby preventing the catalyzed formation of toxic oligomers [19].

Fig. 2

A) An islet with large amounts of amyloid with disrupted islet architecture. Bar 100 µm. B) Electron microscopy image of a beta cell with intracellular islet amyloid polypeptide (IAPP). Insulin constitutes the granule dense core while IAPP occupies the halo region. Arrow indicates proIAPP/IAPP fibrillar material, and asterisks show IAPP amyloid. Bar 250 nm. C) One-letter code of the amino acid sequences of human IAPP and Aβ1–40. D and E) Immunological detection of IAPP and Aβ in amyloid deposits in the brain of a patient with Alzheimer’s disease. Proximity ligation assay (PLA) allows identification of co-localization when antigens are within 40 nm. Red fluorescent dots correspond to positive PLA signals (D). Consecutive section, with amyloid identified by Congo red staining (E). Bar 20 µm.

Fig. 3

Schematic depiction of what is known about the mechanism of transthyretin (TTR) aggregation and how tafamidis (represented by filled rectangles) stabilizes the tetramer, preventing the dissociation of TTR, which is the rate-limiting step of TTR aggregation. It remains unclear how the process of aggregation leads to the loss of certain tissues, but it is clear that several different TTR aggregate structures are formed during aggregation. t=tetramer; m=monomer; mm=misfolded monomer.

Fig. 4

Number of patients transplanted due to transthyretin (TTR) amyloidosis per year and reported to the Familial Amyloidotic World Transplant Registry. The introduction of tafamidis and other drugs under clinical investigation have markedly reduced the transplant activity for this indication.

Fig. 5

A) Mechanism of T119M interallelic trans-suppression of amyloidogenesis. Incorporation of T119M subunits into a transthyretin (TTR) tetramer otherwise composed of amyloidogenic protomers raises the barrier for dissociation proportional to the number of T119M subunits comprising the tetramer. Thus T119M subunit incorporation into the tetramer slows the rate-limiting step of TTR aggregation. B) Linear free energy diagram depicting what is known about the mechanism of TTR aggregation and how tafamidis (represented by filled rectangles) kinetically stabilizes the tetramer, slowing dissociation of TTR, which is the rate-limiting step of TTR aggregation. TTR aggregation is thermodynamically favorable, however the process can be stopped by eliminating the misfolded TTR monomer. t=tetramer; m=monomer; mm=misfolded monomer.

Fig. 5

A) Mechanism of T119M interallelic trans-suppression of amyloidogenesis. Incorporation of T119M subunits into a transthyretin (TTR) tetramer otherwise composed of amyloidogenic protomers raises the barrier for dissociation proportional to the number of T119M subunits comprising the tetramer. Thus T119M subunit incorporation into the tetramer slows the rate-limiting step of TTR aggregation. B) Linear free energy diagram depicting what is known about the mechanism of TTR aggregation and how tafamidis (represented by filled rectangles) kinetically stabilizes the tetramer, slowing dissociation of TTR, which is the rate-limiting step of TTR aggregation. TTR aggregation is thermodynamically favorable, however the process can be stopped by eliminating the misfolded TTR monomer. t=tetramer; m=monomer; mm=misfolded monomer.