Cell reprogramming with Yamanaka factors for treatment of Alzheimer's disease: a study combining human brain organoids and genetically modified animal models

• Grant number: 21/12212-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2022
• End date: September 04, 2026
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Alexandre Hiroaki Kihara
• Grantee: Luciana Simões Rafagnin Marinho
• Host Institution: Centro de Matemática, Computação e Cognição (CMCC). Universidade Federal do ABC (UFABC). Santo André , SP, Brazil
• Associated scholarship(s): 23/13228-1 - Cell reprogramming with Yamanaka factors for treatment of Alzheimer's disease in human brain organoids, BE.EP.PD

Abstract

Alzheimer's disease (AD), characterized by a progressive decline in cognitive function, is the most common form of age-associated neurodegenerative disorder. Neurofibrillary tangles (NFT) are characteristic of AD and have a strong correlation with the cognitive decline and neurodegeneration caused by this disease. 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/c-myc (Yamanaka factors) in genetically modified 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 NFT formation and cognitive capacity in a murine model of frontotemporal lobar degeneration and in human cells from familial Alzheimer's patients, both in 2D cultures and in human brain organoids. Treatment will be evaluated by measuring neuroinflammation and TDP-43 aggregation, transcriptomic analysis by RNAseq and electrophysiological analysis by MEA. The animals will also be submitted to in vivo electrophysiological recordings, evaluation by Barnes labyrinth and analysis of place cell pattern. We emphasize that we master the proposed methodologies as well as the themes studied, what enables us to carry out the experiments within the proposed timeframe.