Utilization of Human Induced Pluripotent Stem Cells-Derived In vitro Models for the Future Study of Sex Differences in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is an aging-dependent neurodegenerative disease that impairs cognitive function. Although the main pathologies of AD are the aggregation of amyloid-beta (Aβ) and phosphorylated Tau protein, the mechanisms that lead to these pathologies and their effects are believed to be heterogeneous among patients. Many epidemiological studies have suggested that sex is involved in disease prevalence and progression. The reduction of sex hormones contributes to the pathogenesis of AD, especially in females, suggesting that the supplementation of sex hormones could be a therapeutic intervention for AD. However, interventional studies have revealed that hormone therapy is beneficial under limited conditions in certain populations with specific administration methods. Thus, this suggests the importance of identifying crucial factors that determine hormonal effects in patients with AD. Based on these factors, it is necessary to decide which patients will receive the intervention before starting it. However, the long observational period and many uncontrollable environmental factors in clinical trials made it difficult to identify such factors, except for the APOE ε4 allele. Induced pluripotent stem cells (iPSCs) derived from patients can differentiate into neurons and recapitulate some aspects of AD pathogenesis. This in vitro model allows us to control non-cell autonomous factors, including the amount of Aβ aggregates and sex hormones. Hence, iPSCs provide opportunities to investigate sex-dependent pathogenesis and predict a suitable population for clinical trials of hormone treatment.

Mutual interaction of neurons and astrocytes derived from iPSCs with APP V717L mutation developed the astrocytic phenotypes of Alzheimer’s disease

“…7 b). ELISA measurement of Aβ 1-42 and Aβ 1-40 confirmed the increased ratio of Aβ 1-42 /Aβ 1-40 in the APP V717L co-culture model compared to the control co-culture model as previously reported [ 17 , 28 ] (Fig. 7 c).…”

“…To examine if our co-culture model can recapitulate the AD-like phenotypes, we co-cultured neurons and astrocytes derived from iPSCs bearing the familial AD (fAD) mutation ( APP V717L ) [ 17 , 28 ]. The iPSC line (APP2E26 line) from a female donor harboring the mutation of familial AD ( APP V717L ) were obtained [ 17 ], and we confirmed a single nucleotide substitution (G > C) at APP Exon 17 (Fig.…”

Estradiol enhanced neuronal plasticity and ameliorated astrogliosis in human iPSC-derived neural models

“…The clinical trials of estrogen replacement therapy to prevent AD development in postmenopausal women resulted in various conclusions. While some clinical studies have suggested the positive effects of E2 in preventing the onset of AD and improving symptoms in patients, some studies concluded that E2 treatment has no significant effects on AD protection (Reviewed in [ 29 ]). To conclude the E2 effects in clinical studies, we conducted a systematic review and meta-analysis of 15 articles related to Alzheimer's disease onset and estrogen replacement therapy, which includes a total of 483,511 patients ( Fig.…”

Role of sex hormones in neuroinflammation in Alzheimer's disease

“…For example, iPS cells can overcome the limitation of species differences among experimental animals and human, and facilitate studies on single cells or the cell-cell interactions. 98,99 Some groups have already demonstrated the roles of E2 100 and testosterone 101 using iPS cells derived from healthy subjects and autism patients, respectively. Such studies involved the analysis of iPS-derived neurons; thus, the effects of sex hormones on iPS-derived glial cells and neuroinflammation could be analyzed in future studies.…”

“…The analysis of sex hormones using induced pluripotent stem (iPS) cells derived from AD patients is useful as a bridge between AD model mice and humans. For example, iPS cells can overcome the limitation of species differences among experimental animals and human, and facilitate studies on single cells or the cell–cell interactions 98,99 . Some groups have already demonstrated the roles of E2 100 and testosterone 101 using iPS cells derived from healthy subjects and autism patients, respectively.…”