Přehled o publikaci

Alzheimer’s disease (AD) is a gradually advancing neurodegenerative disease. With over 55 million people affected worldwide, rising by 10 million annually, AD poses a significant health burden. The primary symptoms of AD involve progressive memory decline and are characterized by two main pathological hallmarks: the buildup of amyloid-β plaques and Tau neurofibrillary tangles formation 1. The majority of the AD cases are sporadic and likely caused by the interaction between the genetic and environmental factors. Only a small percentage of cases belong to the familial form of AD, attributed to mutations in three genes: APP, PSEN1 and PSEN2. Recently, the fourth gene - SORL1 has been associated with the onset of AD2. SORLA protein (encoded by the SORL1 gene) functions as an intracellular sorting receptor managing the sorting and trafficking of intracellular cargo between endosomes and the trans-Golgi network. Specifically, the SORLA protein plays a crucial role in the transport and recycling of the amyloid precursor protein (APP) which directly regulates the processing of the amyloid-β3. Despite individuals with pathological SORLA mutations showing a higher incidence of AD, the precise molecular mechanisms underlying SORLA-dependent AD development remain uncertain. Therefore, more thorough research of this protein and its mutations on a human-relevant model is necessary. To model the AD phenotype in this project, we used induced pluripotent stem cells (iPSCs) carrying selected pathological mutations in the SORL1 gene. Using advanced microscopy techniques and imaging approaches on 2D induced neurons and 3D cerebral organoids we confirmed the presence of key pathological hallmarks of AD: accumulated APP and swollen endosomes. Our results now confirm and visualize how pathogenic mutations of the SORLA protein affect AD development.