Orly Lazarov, PhD

Dr. Orly Lazarov (Department of Anatomy and Cell Biology)

Dr. Jalees Rehman (Department of Biochemistry and Molecular Genetics)

Down Syndrome (DS) as a result of trisomy 21 (T21) results in significant developmental cortical

malformation and invariably accumulation of Alzheimer’s Disease (AD) pathology with aging.

Approximately 70% of people with DS will develop AD by 70 years old. It is theorized that deficits in corticogenesis lead to abnormal neuronal networks vulnerable to the early, pervasive AD pathology observed in DS. Overexpression of amyloid precursor protein (APP) due to T21 is thought to underlie these deficits given its well established role in molecular mechanisms of cortical development and AD. However, given the hundreds of genes located on human chromosome 21 (HSA21), it remains to be established if normalization of APP gene copy number would be sufficient to rescue DS phenotypes. To that end, we have utilized CRISPR-Cas9 technology to eliminate one copy of APP from human DS patientderived induced pluripotent stem cells (iPSCs) {47,XX/Y, 2lAPP} to address the hypothesis APP gene copy number contributes to development of AD phenotypes in Down Syndrome. Isogenic disomy 21 (D21), T21, and T21 with corrected APP iPSC lines will be differentiated into dorsal forebrain organoids. This study will be the first to establish a causative role for APP in DS phenotypes utilizing a 3D human model that temporally recapitulates cell types and structures of the developing cortex. Experiments proposed here aim to establish novel molecular mechanisms for the role of APP in AD in DS and offer potential targets for the development of future therapeutics.