Transcriptomic and metabolomic changes might predict frailty in SAMP8 mice

Frailty is a geriatric multi-dimensional syndrome which reflects multisystem physiological change and is a transversal measure of reduced resilience to negative events. It is characterized by weakness, frequent falls, cognitive decline, increased hospitalization and dead, and represents a risk factor for the development of Alzheimer’s disease (AD). The fact that frailty is recognized as a reversible condition, encourages the identification of earlier biomarkers to timely predict and prevent its occurrence. SAMP8 (Senescence-Accelerated Mouse Prone-8) mice represent the most appropriate preclinical model to this aim and were used in this study to carry transcriptional and metabolic analyses in the brain and plasma respectively, upon a characterization at cognitive, motor, structural and neuropathological level at 2.5, 6 and 9 months of age. At 2.5 months SAMP8 mice started displaying memory deficits, muscle weakness and motor impairment. Functional alterations were associated with a neurodevelopment deficiency associated with reduced neuronal density and glial cell loss. Through transcriptomics we identified specific genetic signatures well distinguishing SAMP8 mice at 6 months and correlating with motor and cognitive dysfunction, whereas plasma metabolomics allowed to segregate SAMP8 mice from SAMR1 already at 2.5 months of age by detecting constitutively lower levels of acylcarnitines and lipids in SAMP8 at all ages investigated. Our findings suggest that specific genetic alterations at central level, as well as metabolomic changes in plasma, might allow to early assess a frail condition leading to dementia development, which paves the foundation for future investigation in a clinical setting. Comparative gene expression profiling analysis of RNA-seq data for SAMP8 with respect to SAMR1 mice in frailty

衰弱（frailty）是一种老年多维度综合征，可反映多系统生理变化，同时是机体对不良事件抗逆能力下降的横向衡量指标。其特征为乏力、频繁跌倒、认知衰退、住院率升高与死亡率上升，且是阿尔茨海默病（AD）发生的风险因素。鉴于衰弱被证实为可逆状态，学界亟需识别早期生物标志物，以实现对其发生的及时预测与预防。快速老化易感小鼠8型（Senescence-Accelerated Mouse Prone-8，SAMP8）是实现该目标的最优临床前模型，本研究以其为对象，分别对脑组织与血浆开展转录组与代谢组分析；实验过程中，研究人员在小鼠2.5、6及9月龄时，从认知、运动、结构及神经病理层面完成了表型表征。2.5月龄时，SAMP8小鼠即开始出现记忆缺陷、肌肉乏力与运动功能损伤。上述功能异常与神经发育缺陷相关，而该缺陷表现为神经元密度降低与胶质细胞丢失。通过转录组学分析，本研究鉴定出可有效区分6月龄SAMP8小鼠的特异性基因特征，且该特征与运动及认知功能障碍存在关联；而血浆代谢组学分析则可在2.5月龄时即区分SAMP8小鼠与快速老化抵抗小鼠1型（SAMR1），其机制为在所有检测月龄中，SAMP8小鼠的酰基肉碱与脂质水平均持续处于较低水平。本研究结果表明，中枢神经系统的特异性基因改变以及血浆代谢组变化，或可实现对引发痴呆的衰弱状态的早期评估，为后续临床相关研究奠定了基础。本研究同时完成了针对SAMP8与SAMR1小鼠衰弱相关表型的RNA测序数据比较基因表达谱分析。