Alzheimer's disease (AD) is a devastating pathology of the central nervous system (CNS) of unknown etiology which represents the most common neurodegenerative disorder. For decades, AD was perceived as a disease of the neuron alone. However, research advances in recent years have challenged this concept and shed light on the critical roles of non-neuronal cells on the development and progression of AD. In my PhD, I focused on understanding how two non-neuronal cell types - the Astrocytes and Microglia - respond to AD and how they possibly affect pathological processes. Our research identified a unique population of Astrocytes that significantly increased in association with brain pathology, which we termed disease-associated astrocytes (DAAs). This novel population of DAAs appeared at an early disease stage, increased in abundance with disease progression, and was not observed in young or in healthy adult animals. In addition, similar astrocytes appeared in aged wild-type (WT) mice and in aging human brains, suggesting their linkage to genetic and age-related factors. Aging is considered the greatest risk factor for AD, although the mechanism underlying the aging-related susceptibility to AD is unknown. One emerging factor that is involved in biological aging is the accumulation of senescent cells. Cellular senescence is a process in which aging cells change their characteristic phenotype. Under physiological conditions senescent cells can be removed by the immune system, however with aging, senescent cells accumulate in tissues, either due to a failure of effective removal or due to the accelerated formation of senescent cells.
Our data highlight the contribution of non neuronal cells to AD pathogenesis by demonstrating that 1. Overexpression of a specific gene by astrocytes affected the microglia cells' state, leading to a more homeostatic and less reactive microglial phenotype in comparison to the control group. 2. Accumulation of senescent microglia cells was observed in the brain of aged WT mice and AD mouse model (5xFAD), and by applying different therapeutic strategies we managed to observe significant quantitative differences in these cells, followed by a cognitive amelioration.
