ELECTROPHYSIOLOGICAL PROPERTIES OF HUMAN NEURONS DERIVED FROM PATIENTS WITH ALZHEIMER'S DISEASE

The presymptomatic stage of Alzheimer’s disease (AD) is currently the most promising phase for identifying biomarker candidates and developing potential therapeutic interventions. AD can present as either sporadic (SAD) or familial (FAD). Although the familial form accounts for only approximately 2% of AD cases, it enables early diagnosis and provides valuable insight into the key molecular and cellular changes associated with disease progression. In this study, we utilize human induced pluripotent stem cells (hiPSCs) derived from fibroblasts of AD patients (both FAD and SAD), healthy family members, and unrelated control individuals. Our experimental models include cortical brain organoids and two-dimensional neuronal cultures. The aim of this research is to characterize synaptic deficits associated with disease progression, with a primary focus on excitotoxicity as a major contributor to neurodegeneration. To assess these deficits, we employ calcium imaging, intracellular recordings, and multielectrode array (MEA) recordings. Our results reveal significant differences in calcium homeostasis between AD patients and healthy controls, evident both at baseline and following neuronal stimulation. We also observed alterations in the discharge patterns of spontaneous synaptic activity, as well as differences in action potential amplitude and firing rate. MEA recordings further demonstrated disruptions in neural network firing synchrony in AD-derived cultures. Collectively, these findings suggest that excitotoxicity plays a significant role in AD-related neurodegeneration and that these pathological events are already present during the presymptomatic stage of the disease.