Project Summary Brain aging is characterized by reduced cognitive capacities, learning and memory. The exact mechanisms of brain aging remain elusive. Because aging is the greatest risk factor for major debilitating neurodegenerative disorders, including Alzheimer's disease (AD), it is important to uncover mechanisms underlying brain aging in order to develop effective therapies for age-related neurodegenerative diseases. AD is the most common neurodegenerative disorder and a leading cause of disability and death. However, the precise mechanisms underlying AD pathogenesis remains to be elucidated. Although many transgenic mouse models have been generated for AD research and these models are important for our understanding of the pathological basis of the disease, it is increasingly recognized that there are significant species differences between mouse and human neural cells. Therefore, there is an urgent need to establish human disease modeling platforms to complement studies in animal models for AD research. Direct reprogramming is a cellular reprogramming technology, which allows direct conversion of one type of somatic cells, such as fibroblasts, into another type of somatic cells, such as neurons. It has been shown that direct reprogramming enables generation of human neurons that possess key elements of cellular aging. Therefore, directly reprogrammed cells could provide a human cellular platform for us to model brain aging and age-related late-onset diseases, such as late-onset AD (LOAD). The objective of this proposal is to develop human age-relevant glial cellular models using direct reprogramming technology, in order to recapitulate age-associated phenotypes in brain aging and neurodegeneration and uncover novel underlying mechanisms. Increasing evidence suggests that astrocytes play important roles in brain health and pathogenesis of neurodegenerative diseases. Therefore, we propose to establish cellular models for brain aging and AD using astrocytes directly reprogrammed from fibroblasts of aged subjects and LOAD patients and co-cultures of astrocytes with other brain cell types, including microglia, oligodendrocytes, and neurons. We hypothesize that cellular aging regulates astrocyte function and cell-cell interactions to modulate brain aging phenotypes and LOAD pathologies. Accordingly, we propose the following Specific Aims:Aim 1: To generate age-associated astrocytes through direct reprogramming and evaluate how cellular aging regulates astrocytic functions. Aim 2: To determine whether and how astrocytic cellular aging modulates neuroinflammation and neuronal phenotypes. Aim 3: To determine whether and how astrocytic cellular aging regulates OPC properties and myelination. The proposed studies will likely help to define roles of glial cellular aging in brain functional deterioration during aging and uncover the underlying mechanisms, which could lead to the development of novel strategies to maintain brain health and reduce ri...