患有早期家庭AD的个体(即65岁之前,但最早30岁)构成了一小部分AD患者。可能显示出常染色体的遗传模式。在受影响的家族中已经鉴定出三个基因的致病突变:淀粉样蛋白β前体蛋白基因(APP),Presenilin 1(PSEN1)基因和Presenilin 2(PSEN 2)基因。APP和PSEN1致病变异具有100%的其他原因死亡,而PSEN 2具有95%的渗透率。这些基因中的各种变体与AD相关。 PSEN1中的变体似乎是最常见的。虽然只有3%–5%的AD患者患有早期疾病,但在这些患者中,已确定了多达70%或更多的病原变异。可识别的遗传变异是AD的罕见原因。
Presenilin(PSEN)基因中的突变是早期发作家族性阿尔茨海默氏病(FAD)的最常见原因。在细胞培养,体外生化系统和敲除小鼠中的研究表明,PSEN突变是功能丧失突变,损害了γ-泌尿酶活性。小鼠遗传分析强调了presenilin(PS)在学习和记忆,突触可塑性和神经递质释放以及神经元存活中的重要性,而果蝇研究进一步证明了PS在老化过程中PS在神经元存活中的进化作用。然而,在神经元存活中与PS相互作用的分子途径尚不清楚。为了调节PS依赖性神经元存活的遗传修饰符,我们开发了一种新的果蝇PSN模型,该模型表现出年龄依赖性神经变性和凋亡的增加。经过生物信息学分析,我们使用PSN KD模型中的两个独立的RNAi系在神经元中的每个基因的选择性敲低(KD)测试了排名最高的候选基因。有趣的是,在脂质转运和代谢中,增强PSN KD蝇中神经退行性的9个基因中有4个。具体而言,LPR1和LPR2的神经元特异性KD急剧恶化了PSN KD蝇中的神经退行性,LPR1或LPR2的过表达不会减轻PSN KD KD诱导的神经变性。此外,仅LPR1或LPR2 KD也会导致神经退行性,凋亡增加,攀爬缺陷和寿命缩短。这些发现表明,LPRS调节了依赖PSN的神经元存活,对于衰老大脑的神经元完整性至关重要。最后,LPR1和LPR2的杂合缺失或LPR1或LPR2的纯合缺失类似导致PSN KD Flies中的年龄依赖性神经变性,并进一步加剧神经变性。
1, SFEBq = serum-free floating culture of em- bryoid body-like aggregates with quick aggrega- tion, CGE = Caudal Ganglionic Eminence, SS = Subpallium Spheroids, SAG = Smoothened Agonist, CXCR4 = Chemokine Receptor type 4, CO = Cortical Organoids, ALI-Cos = Air-Liquid Interface culture to Cerebral Organoids, MPCs = Mesoderm Progenitor Cells, IBA1 = Ionized calcium-Binding Adapter molecule 1, WDR62 = WD Repeat domain 62, KIF2A = Kinesin Fam- ily Member 2A, CEP170 = Centrosomal Protein 170, NARS1 = asparaginyl-tRNA synthetase 1, RGC = Radial Glial Cells, CNV = Copy Num- ber Variation, PTEN = Phosphatase and Tensin homolog, ODC1 = Ornithine Decarboxylase 1, PKB = Protein Kinase B, ASDs = Autism Spec- trum Disorders, FOXG1 = Forkhead Box G1, CHD8 = Chromodomain Helicase DNA-bind- ing protein 8, DEGs = Differentially Expressed Genes, DISC1= Disrupted-in-Schizophrenia 1, GSK3 = Glycogen Synthase Kinase 3, RTT = Rett Syndrome, MeCP2 = Methyl-CpG-binding protein 2, ERK = Extracellular signal-Regulated Kinase, MAPK = Mitogen-Activated Protein Ki- nase, MDS = Miller-Dieker Syndrome, AD = Alzheimer's Disease, APP = Amyloid Precursor Protein, PSEN = Presenilin, APOE = Apoli- poprotein E, NFT = NeuroFibrillary Tangles, MMP = Metalloproteinase, PD = Parkinson's Disease , SNCA = Synuclein Alpha, LRRK2 = Leucine Rich Repeat Kinase 2, HD = Huntigton's Disease, GSCs = Cancer Stem Cells, GBOs = Glioblastoma Organoids, TBI = Traumatic Brain Injury, CCI = Controlled Cortical撞击,NSE =神经元特异性烯醇酶。