Cell reprogramming with Yamanaka factors for treatment of Alzheimer's disease in human brain organoids

• Grant number: 23/13228-1
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: November 01, 2024
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Alexandre Hiroaki Kihara
• Grantee: Luciana Simões Rafagnin Marinho
• Supervisor: Alysson Renato Muotri
• Host Institution: Centro de Matemática, Computação e Cognição (CMCC). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil
• Institution abroad: University of California, San Diego (UC San Diego), United States
• Associated to the scholarship: 21/12212-9 - Cell reprogramming with Yamanaka factors for treatment of Alzheimer's disease: a study combining human brain organoids and genetically modified animal models, BP.PD

Abstract

Alzheimer's disease (AD), characterized by a progressive decline in cognitivefunction, is the most common form of age-associated neurodegenerative disorder. AD is characterized by two core pathologies, extracellular amyloid-beta (A²) plaques and aggregated tau protein forming intra-neuronal neurofibrillary tangles (NFT), culminating in a reduction in synaptic strength, synaptic loss, and neurodegeneration. The susceptibility of older individuals to neurodegenerative diseases is due to changes that progressively occur in the nervous system; however, genetic and epigenetic manipulations appear to increase life expectancy and improve certain age-related phenotypes. Induction of expression of the reprogramming factors Oct4, Sox2, KLF4 and c-myc (Yamanaka factors) in genetically modified and wild-type mice increased life span, improved injury recovery, and was the first treatment to restore vision after acute or chronic damage to the CNS. This study aims to investigate the effect of cyclic induction of the expression of Yamanaka factors in reducing the phenotypes associated with AD in human brain organoids derived from induced-pluripotent cells from familial Alzheimer's patients. Treatment will be assessed by evaluating neuroinflammation and TDP-43 aggregation, transcriptomic analysis by RNAseq and electrophysiological analysis by MEA.