Role of Cholesterol and Phospholipids in Amylin Misfolding, Aggregation and Etiology of Islet Amyloidosis

Abstract

Amyloidosis is a biological event in which proteins undergo structural transitions from soluble monomers and oligomers to insoluble fibrillar aggregates that are often toxic to cells. Exactly how amyloid proteins, such as the pancreatic hormone amylin, aggregate and kill cells is still unclear. Islet amyloid polypeptide, or amylin, is a recently discovered hormone that is stored and co-released with insulin from pancreatic islet β-cells. The pathology of type 2 diabetes mellitus (T2DM) is characterized by an excessive extracellular and intracellular accumulation of toxic amylin species, soluble oligomers and insoluble fibrils, in islets, eventually leading to β-cell loss. Obesity and elevated serum cholesterol levels are additional risk factors implicated in the development of T2DM. Because the homeostatic balance between cholesterol synthesis and uptake is lost in diabetics, and amylin aggregation is a hallmark of T2DM, this chapter focuses on the biophysical and cell biology studies exploring molecular mechanisms by which cholesterol and phospholipids modulate secondary structure, folding and aggregation of human amylin and other amyloid proteins on membranes and in cells. Amylin turnover and toxicity in pancreatic cells and the regulatory role of cholesterol in these processes are also discussed.

In situ characterization of protein aggregates in human tissues affected by light chain amyloidosis: a FTIR microspectroscopy study

“…Co-localization of cholesterol and amyloid fibrils is also well documented in the case of Aβ amyloid plaques 60 61 , whereas, to our knowledge, this is the first report of the enrichment of this lipid in amyloid-positive regions in AL amyloidosis. Although these observations strongly suggest a pathophysiological role of cholesterol in protein misfolding diseases, the precise contribution of this and other lipids in amyloid pathology is still matter of study 62 63 64 . This aspect has been especially investigated in Alzheimer’s disease, in which generation and clearance of Aβ protein, and its interaction with cells and membranes, are influenced by this molecule 65 66 .…”

C4b-binding Protein Protects β-Cells from Islet Amyloid Polypeptide-induced Cytotoxicity

“…Direct contact of IAPP aggregates with cell membranes is needed to elicit apoptosis (18), which may proceed because of membrane destabilization and cation channel formation in cell membranes (17,33). Cholesterol plays an important role in IAPP fibrillation and oligomer toxicity (34). Although IAPP fibrillation is enhanced by the presence of negatively charged phospholipids, addition of cholesterol to such anionic membranes had the opposite effect (35).…”

Connecting Alzheimer’s Disease With Diabetes Mellitus Through Amyloidogenic Evolvability

“…In this regard, evolvability of APs, including Aβ and tau, might be increased through mechanisms other than aggregative protein-protein interactions. For instance, cholesterol, which may play a central role in dyslipidemia, might stimulate misfolding and aggregation of APs in evolvability as well as in neurodegeneration and T2DM (Singh et al, 2015). Also, catecholamines possibly related to essential hypertension might be relevant (Goldstein, 1983).…”

“…Given analogous pathology between T2DM and neurodegenerative disorders in terms of amyloidosis-associated stressors (Abedini and Schmidt, 2013;Singh et al, 2015), common mechanisms might form the basis for both groups of disorders. In this context, the main objective of this article is to discuss the mechanisms by which T2DM might increase AD risk from the viewpoint of amyloidogenic evolvability.…”