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 amyloid β-peptide (Aβ) plaques and tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with vaccines and small molecules to target Aβ formation and aggregation and also 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 disease is linked to the aggregation and progressive accumulation of islet amyloid polypeptide and oligomers of this peptide 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 be conducted to determine their efficacy in vivo. Transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases involving multiple organ systems and 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, non-amyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as treatment.

A Dormant Microbial Component in the Development of Preeclampsia

“…New drugs designed to kill non-growing bacteria (1286–1290) or to overcome amyloid coagulopathies (1291–1295) will be needed and will come to the fore.…”

New Insight in The Molecular Mechanisms of Neurodegenerative Disease

“…AD is an example of a localized cerebral amyloidosis and type 2 diabetes mellitus is an example of localized extracerebral amyloidosis; both diseases are associated with aging. (206) Transthyretin (TTR) (207), immunoglobulin light chain (LC) (208), serum amyloid A (SAA) (209), and Aβ (210) are examples of more than thirty human proteins whose misfolding and/or misassembly into a variety of aggregate structures appear to cause a spectrum of degenerative disorders (211). These so-called amyloid diseases are named after the cross-β-sheet aggregates, or amyloid fibrils, that are the pathological hallmarks of these maladies.…”

Transthyretin—A Key Gene Involved in Regulating Learning and Memory in Brain, and Providing Neuroprotection in Alzheimer Disease via Neuronal Synthesis of Transthyretin Protein

“…TTR suppressed Aβ and prevent its toxicity [89] [90]. Studies showed that TTR sequestered Aβ in the CSF and J. Iqbal Journal of Behavioral and Brain Science moved Aβ to the choroid plexus (CP) for enzymatic degradation and removal from the brain [18].…”