Delineation of Alzheimer's Disease initiation and propagation using novel adult human brain organoids

About This Grant

Abstract Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by the progressive degeneration of neurons, leading to cognitive decline. Cumulatively, over 10% of people over the age of 65 have AD, higlighting an urgent need for innovative therapeutic targets, particularly as the rate of AD continues to rise globally. Previous research has focused on key hallmarks of AD including neurofibril tau tangles and amyloid- beta (Aβ) plaques primarily in neuronal cells. However, emerging evidence suggests that non-neuronal cells, including microglia and vascular cells, play a critical role in both the initiation and progression of AD. This proposal aims to leverage a groundbreaking air-liquid interface (ALI) adult human brain organoid culture system, which co-preserves diverse cell types including neurons, oligodendrocytes, astrocytes, endothelial cells, pericytes, and microglia, to comprehensively explore the underlying mechanisms of AD focusing on tau and/or Aβ as disease drivers. These aims determine the cell types responsible for tau and Aβ seeding and spread, characterizing the influence of microglia and endothelial cells on Aβ aggregation and tau spread, and elucidating the sequential dynamics of tau and Aβ in disease phenotype development. Specifically, Aim 1 identifies cell types responsible for primary Ab and tau seeding and secondary spread of “prion-like” aggregates phenotypes. Aim 2 determines the role of microglia in Ab and tau deposition and spread. Aim 3 determines the role of the vasculature in AD spread and identifies biomarkers for early AD. Through these studies, the goal is to provide critical insights into the contributions of the neurovascular microenvironment inclusive of microglia on AD initiation and spread, with potential implications for identifying novel therapeutic strategies aimed at mitigating disease progression. The proposed experiments will span the entire award period, with the technical training Dr. Rada receives during the mentored phase laying the groundwork for her independent research. A dedicated team of expert mentors and mentoring committee will provide her with instruction in essential methods that are crucial for the success of her studies on AD. In addition to hands-on training, Dr. Rada will actively participate in local and national meetings and scientific conferences to expand her network, enhance the visibility of her work, and stay current with advancements in the AD field. She will also attend career planning courses and meet regularly with her mentors and advisory committee to discuss her scientific progress, as well as to strategically prepare for job applications and interviews. Both of Dr. Rada’s co-mentors are fully committed to her success, ensuring she is well-equipped to carry her innovative research plan forward as she transitions to establishing an independent academic research lab.