Linking Alzheimer’s Disease and Type 2 Diabetes: Characterization and Inhibition of Cytotoxic Aβ and IAPP Hetero-Aggregates

Abstract

The cytotoxic self-aggregation of β-amyloid (Aβ) peptide and islet amyloid polypeptide (IAPP) is implicated in the pathogenesis of Alzheimer’s disease (AD) and Type 2 diabetes (T2D), respectively. Increasing evidence, particularly the co-deposition of Aβ and IAPP in both brain and pancreatic tissues, suggests that Aβ and IAPP cross-interaction may be responsible for a pathological link between AD and T2D. Here, we examined the nature of IAPP-Aβ40 co-aggregation and its inhibition by small molecules. In specific, we characterized the kinetic profiles, morphologies, secondary structures and toxicities of IAPP-Aβ40 hetero-assemblies and compared them to those formed by their homo-assemblies. We demonstrated that monomeric IAPP and Aβ40 form stable hetero-dimers and hetero-assemblies that further aggregate into β-sheet-rich hetero-aggregates that are toxic (cell viability <50%) to both PC-12 cells, a neuronal cell model, and RIN-m5F cells, a pancreatic cell model for β-cells. We then selected polyphenolic candidates to inhibit IAPP or Aβ40 self-aggregation and examined the inhibitory effect of the most potent candidate on IAPP-Aβ40 co-aggregation. We demonstrated that epigallocatechin gallate (EGCG) form inter-molecular hydrogen bonds with each of IAPP and Aβ40. We also showed that EGCG reduced hetero-aggregate formation and resulted in lower β-sheets content and higher unordered structures in IAPP-Aβ40-EGCG samples. Importantly, we showed that EGCG is highly effective in reducing the toxicity of IAPP-Aβ40 hetero-aggregates on both cell models, specifically at concentrations that are equivalent to or are 2.5-fold higher than the mixed peptide concentrations. To the best of our knowledge, this is the first study to report the inhibition of IAPP-Aβ40 co-aggregation by small molecules. We conclude that EGCG is a promising candidate to prevent co-aggregation and cytotoxicity of IAPP-Aβ40, which in turn, contribute to the pathological link between AD and T2D.

APPI-Derived Cyclic Peptide Enhances Aβ42 Aggregation and Reduces Aβ42-Mediated Membrane Destabilization and Cytotoxicity

“…Since the cyclic peptide alone did not generate any detectable CD signal, the enhancement of the CD signal may be attributed to the interaction of Aβ42 with the cyclic peptide. The calculated sum of the CD ellipticity values of the spectra of the cyclic peptide and Aβ42 differed from the spectrum obtained for the Aβ42/cyclic peptide mixture, indicating the existence of interactions between Aβ42 and the cyclic peptide (a method of analysis described in previous reports). − Importantly, the formation of the β-sheet structure in freshly dissolved Aβ42 in the presence of the cyclic peptide was detected immediately upon addition of the cyclic peptide to the Aβ42 solution (i.e., at incubation time 0), whereas Aβ42 alone showed a predominantly random structure with a typical minimum at 197 nm (Figure S5A). , Here again, the calculated sum of the individual spectra of Aβ42 and the cyclic peptide (when measured separately) differed from the CD spectrum that was obtained for the mixture, indicating that Aβ42-cyclic peptide interactions occurred immediately upon mixing the peptides.…”

Effect of Bacterial Amyloid Protein Phenol−Soluble Modulin Alpha 3 on the Aggregation of Amyloid Beta Protein Associated with Alzheimer’s Disease

“…According to the above results, it can be concluded that the cross−interaction between the PSMα3 monomer and the Aβ 40 monomer resulted in the formation of non−fibrillar heterogeneous aggregates (Figure 1c), similar to the hetero−oligomers formed by Aβ and human islet amyloid polypeptide (hIAPP) [39,40] or tau [41]. These heterogeneous structures interfered with the conformational transitions of Aβ 40 , resulting in reduced ThT fluorescence (Figure 1a).…”

Elementary Pathophysiology, Treatment, Risk Factor of Alzheimer’s Disease

“…Cerebrovascular abnormalities such as haemorrhagic infarcts, minor and large ischemic cortical infarcts, vasculopathies, and changes in cerebral white matter have all been linked to an increased risk of dementia. Post-mortem examinations of the brains of Alzheimer's disease patients reveal the existence of parenchymal vascular disease (amyloid angiopathy by Aβ peptide and small channel arteriolosclerosis illness), with haemorrhagic breakouts and infarcts observed in more than half of them [143][144]. According to neuropathological results, between 6 to 47 percent of those with dementia have cerebrovascular disease.…”