Islet Amyloid Polypeptide Modelled to Simulate Diabetes Co‐Oligomerized with β‐Amyloid 1‐42 Reproducing the Pathological Cascade of Alzheimer's Disease in Human Cerebral Organoids

ABSTRACT Previous animal models of sporadic Alzheimer's disease (sAD), based on the β‐amyloid (Aβ) cascade hypothesis and induced by Aβ1‐42 oligomers (AβO), only recapitulated early AD pathological features. sAD cerebral organoids (COs) model employed Aβ coculture approach and found no typical features of AD pathology. Type 2 diabetes (T2DM) is one of the most important modifiable AD risk factors, so we hypothesize that T2DM could substantially exacerbate Aβ neurotoxicity and reproduce typical AD pathology. Human islet amyloid polypeptide (hIAPP) was used to mimic T2DM and was co‐oligomerized with Aβ1‐42 peptide, and delivered to the central of human iPSC‐derived mature COs through intermittently repeated microinjections, so as to simulate the chronic exposure to Aβ within the brain. The Aβ42‐hIAPP co‐oligomers induced a pathological phenotype more closely resembling the pathological features of advanced AD, notably, neuronal density showed significant reduction, with 3.2 times more neuronal death. Dynamic metabolomic analysis revealed the metabolic pathways and differential metabolites that may be correlated to the primary mechanism underlying the enhanced neurotoxic effects and accelerated AD pathology. Furthermore, this study developed a sAD CO model more resembling the pathological features of advanced AD, which potentially provides a valuable platform for AD pathogenesis research and novel drug screening.