Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells

Abstract

Human pancreatic islet amyloid polypeptide (hiApp) and beta amyloid (Aβ) can accumulate in Type 2 diabetes (T2D) and Alzheimer's disease (AD) brains and evidence suggests that interaction between the two amyloidogenic proteins can lead to the formation of heterocomplex aggregates. However, the structure and consequences of the formation of these complexes remains to be determined. The main objective of this study was to characterise the different types and morphology of Aβ-hiApp heterocomplexes and determine if formation of such complexes exacerbate neurotoxicity. We demonstrate that hiApp promotes Aβ oligomerization and formation of small oligomer and large aggregate heterocomplexes. Co-oligomerized Aβ42-hIAPP mixtures displayed distinct amorphous structures and a 3-fold increase in neuronal cell death as compared to Aβ and hIAPP alone. However, in contrast to hIAPP, non-amyloidogenic rat amylin (rIAPP) reduced oligomer Aβ-mediated neuronal cell death. rIAPP exhibited reductions in Aβ induced neuronal cell death that was independent of its ability to interact with Aβ and form heterocomplexes; suggesting mediation by other pathways. Our findings reveal distinct effects of IAPP peptides in modulating Aβ aggregation and toxicity and provide new insight into the potential pathogenic effects of Aβ-IAPP hetero-oligomerization and development of IAPP based therapies for AD and T2D. Epidemiological and clinical evidence suggests a strong association between Type 2 diabetes (T2D) and Alzheimer's disease (AD), with T2D patients having a significantly higher risk of developing AD compared to non-diabetic individuals 1-3. Both AD and T2D share common pathogenic markers including inflammation, oxidative stress, metabolic dysfunction and accumulation of the amyloidogenic proteins including beta amyloid (Aβ) and pancreatic islet amyloid polypeptide (IAPP or amylin) 4,5. Aβ is the main component of senile plaques in the AD brain 6. Similar to Aβ, human IAPP (hIAPP) containing deposits are observed in the T2D pancreas 7. The accumulation of aggregated Aβ or hIAPP in the brain and pancreas has been shown to be associated with cell dysfunction and death 8,9. Aβ is produced via the N-terminal proteolytic cleavage of amyloid precursor protein (APP) by BACE1 and at the C-terminus by γ-secretase, with the final Aβ length varying from 39 to 43 amino acids 10. Aβ42 is the central component of senile plaques observed in the AD brain and is considered the main neurotoxic form 11,12. hIAPP is cleaved from the pre-pro form of IAPP and subsequently converted into a 37-amino acid structure by pancreatic β-cell secretory granules 7. Mature hIAPP modulates insulin-sensitive glucose uptake and

Degradation of Alzheimer’s amyloid-β by a catalytically inactive insulin-degrading enzyme

“…Additionally, we expect that the reported findings to have high impacts in the field as an increase in the risk of T2D in AD [57] or vice-versa and cross-seeding among various amyloidogenic proteins, including Aβ and amylin, remarkably highlight the pathological correlation between AD and T2D. [58] In conclusion, we have demonstrated the proteolytic activities of wild-type and cysteine-free E111Q mutant IDEs on Aβ . Both IDEs were found to be catalytically active and able to cleave Aβ monomers to short fragments.…”

Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?

“…Once formed, the rapid elongation phase begins as the recruitment of monomeric proteins is added to the aggregated mass due to thermodynamically favorable interactions, forming insoluble complexes [53]. As the intermediate and end products of all amyloid aggregations have common β-sheet structures, different amyloids such as IAPP and Aβ have been shown to actively interact and form hetero-oligomer and hetero-fibril complexes [17,54].…”

“…Recent studies indicate that IAPP may travel systemically from the pancreas and cross the blood-brain barrier (BBB) to deposit with Aβ plaque in the brain [14,56]. Co-oligomerized IAPP-Aβ complexes can increase neuronal cell death up to 3-fold compared to similar concentrations of IAPP or Aβ alone [17]. Interestingly, peripherally produced amylin can bind to amylin receptors in the endothelial cells of the BBB, increasing the translocation of Low-density Lipoprotein Receptor-Related Protein 1 (LRP1) to the cell membrane and thereby actively promoting the transport of brain Aβ into the blood [57].…”

“…Once co-localized, Aβ and IAPP may also undergo a process called cross-seeding, where the aggregation and seeding of amyloidogenic peptides attract and aggregate with more similar and/or different types of amyloidogenic peptides [15,16]. In this case, co-localized Aβ and IAPP may promote the formation of combined Aβ-IAPP oligomeric hetero-complexes [17][18][19]. Such dysfunctions in the protein homeostasis of vital tissues often create a stressful environment in which cells may fail to thrive.…”

β-Hairpin Peptide Mimics Decrease Human Islet Amyloid Polypeptide (hIAPP) Aggregation

“…Cardiovascular complications affect around 65% of T2D patients despite medication and hIAPP aggregates mediates cardiotoxicity ( Despa et al, 2014 ; Rodriguez Camargo et al, 2018 ). Furthermore, T2D has been recognized as a risk factor for Alzheimer’s disease (AD) and cross-amyloid interactions between hIAPP and amyloid-β peptide (Aβ 1–42 ) have been shown to play a critical role in AD due to an increased toxicity of Aβ-IAPP hetero-oligomerization on neuronal cell membranes ( Roriz-Filho et al, 2009 ; Bharadwaj et al, 2020 ; Ly et al, 2021 ). A cross interaction between hIAPP and synuclein has been also suspected to also explain why patients with T2D are more likely to get Parkinson’s disease ( Horvath and Wittung-Stafshede, 2016 ).…”