Harvard Medical School, Boston, MA, USA; Program for Neuropsychiatric Research, McLean Hospital, 115 Mill St., Belmont, MA 02478, USA.
Harvard Medical School, Boston, MA, USA; Laboratory for Translational Research on Neurodegeneration, Program for Neuropsychiatric Research, McLean Hospital, 115 Mill St., Belmont, MA 02478, USA.
EBioMedicine. 2024 Aug;106:105238. doi: 10.1016/j.ebiom.2024.105238. Epub 2024 Jul 12.
Most cases of Alzheimer's disease (AD) are late-onset dementias (LOAD). However, research on AD is predominantly of early-onset disease (EOAD). The determinants of EOAD, gene variants of APP and presenilin proteins, are not the basic precursors of LOAD. Rather, multiple other genes and associated cellular processes underlie risk for LOAD. These determinants could be modified in individuals at risk for LOAD well before signs and symptoms appear. Studying brain cells produced from patient-derived induced-pluripotent-stem-cells (iPSC), in culture, will be instrumental in developing such interventions. This paper summarises evidence accrued from iPSC culture models identifying the earliest occurring clinically targetable determinants of LOAD. Results obtained and replicated, thus far, suggest that abnormalities of bioenergetics, lipid metabolism, digestive organelle function and inflammatory activity are primary processes underlying LOAD. The application of cell culture platforms will become increasingly important in research and also on LOAD detection, assessment, and treatment in the years ahead.
大多数阿尔茨海默病（AD）病例为迟发性痴呆（LOAD）。然而，AD 的研究主要针对早发性疾病（EOAD）。EOAD 的决定因素，即 APP 和早老素蛋白的基因突变，并不是 LOAD 的基本前体。相反，LOAD 的风险是由多个其他基因和相关细胞过程引起的。这些决定因素可能会在出现迹象和症状之前很久就在 LOAD 高危个体中得到改变。研究来自患者衍生的诱导多能干细胞（iPSC）的脑细胞在培养中对于开发这种干预措施将是非常重要的。本文总结了从 iPSC 培养模型中获得的证据，这些证据确定了 LOAD 最早出现的临床可靶向决定因素。迄今为止获得并复制的结果表明，生物能量、脂质代谢、消化细胞器功能和炎症活性异常是 LOAD 的主要发生过程。细胞培养平台的应用在未来几年的研究以及 LOAD 的检测、评估和治疗方面将变得越来越重要。
