Imipramine treatment reduces Alzheimer’s disease neuropathologies in cerebral organoid models of Alzheimer’s disease and Down syndrome

Abstract

AbstractBackgroundFamilial Alzheimer’s disease (fAD) is a autosomal dominant, early‐onset form of AD caused by genetic mutations such as duplication of the amyloid precursor protein gene (APP) on one chromosome (APPdup) or point mutations in APP such as the London mutation (APPV717I), both of which cause overproduction of the amyloid‐beta peptide (Aβ). People with Down syndrome (DS) also have a form of fAD due to triplication of APP which resides on chromosome 21. By age 40, all people with DS develop AD brain pathology, including Aβ plaques and neurofibrillary tangles of phosphorylated tau (pTau), and most go on to develop early‐onset dementia. We previously identified imipramine by high‐throughput screening for novel inhibitors of apolipoprotein E (apoE), which is the strongest risk factor for AD other than age itself. Here, we developed and characterized new cerebral organoid (CO) models of fAD and DS and used them to study common pathological mechanisms and to evaluate imipramine as a novel AD treatment.MethodWe obtained human induced pluripotent stem cells (hiPSCs) from multiple donors with fAD (APPdup or APPV717I), DS, or healthy controls (HC), all with the APOE3/3 genotype, and generated COs using validated techniques. We treated COs beginning at 45 days in vitro with 1 or 10 μM imipramine in the culture medium, and we collected treated and untreated organoids after 120 days for analysis by immunoblotting, immunohistochemistry, and ELISA.ResultCOs from fAD or DS donors were significantly reduced in size compared to those from HC donors. Increased expression of APP, Aβ, pTau, and apoE were observed in fAD and DS COs relative to HC COs. Levels of Aβ and apoE were positively correlated in all COs. Imipramine treatment significantly reduced the levels of some neuropathologies in AD COs, but did not affect the size or cellular composition of HC COs.ConclusionWe characterized several new CO models of fAD and DS, which will be useful for identifying commonalities in disease mechanisms as well as for dissecting the roles of chromosome 21 genes other than APP. Our results indicate that imipramine and other therapeutics targeting the role of apoE are promising approaches to treating AD.