Interaction of human IAPP and Aβ1-42 aggravated the AD-related pathology and impaired the cognition in mice.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) have a common pathology. Both diseases are characterized by local deposition of amyloid proteins in the brain or islet organ, but their phenotypes and clinical manifestation vary widely. Although the sources of islet amyloid polypeptide (IAPP) and amyloid beta (Aβ) are independent, their fibrillar sequences are highly homologous. The prevalence of AD in T2DM populations is considerably higher than that in the normal population, but a mechanistic linkage remains elusive. Therefore, the present study aimed to explore the effects of Aβ42 deposition in the brain on the persistently expression of human IAPP (hIAPP). Additionally, cognitive ability, synaptic plasticity, the state of neural stem cells and mitochondrial function were evaluated at 2 or 6 months after stereotaxically injected the oligomer Aβ1-42 into the dentate gyrus of hIAPP (-/+) mice or the wild-type littermates. We found that Aβ42 and amylin were co-located in hippocampus and Aβ42 levels increased when Aβ1-42 was injected in hIAPP transgenic mice compared with that of the wild-type littermates. Furthermore, at 6 months after Aβ1-42 injection in hIAPP (-/+) mice, it exhibits exacerbated AD-related pathologies including Aβ42 deposition, cognitive impairment, synapse reduction, neural stem cells exhaustion and mitochondrial dysfunction. Our present study suggested that hIAPP directly implicated the Aβ42 production and deposition as an important linkage between T2DM and AD.