La risposta eterogenea degli astrociti alla malattia di Alzheimer: focalizzazione sui cambiamenti funzionali e morfologici

Unlike central nervous system (CNS) neurons which exhibit a high degree of diversity, astrocytes have traditionally been considered homogenous. Although recent studies have challenged this belief, there has been no broad assessment of astrocyte diversity and similarity across the CNS. An important goal, therefore, is to understand the molecular similarities and differences among astrocytes in the CNS and to determine how these properties relate to normal conditions and disease. For this purpose, Endo and colleagues evaluated astrocyte regional diversities analyzing 13 different CNS regions. They demonstrated that astrocytes have molecular features and functions specific to CNS regions. These region-specific functions arise from the variable representation of seven distinct astrocyte subclusters. They also suggested the involvement of environmental cues in the definition of astrocyte heterogeneity of different regions. Furthermore, they identified gene networks related to astrocyte morphology, and they observed that the knockdown of key morphology-related genes impair cognitive tasks, indicating that astrocyte morphological changes affect neural circuit function. In addition, they found that some of the astrocyte morphology-related genes such as Apoe, Clu, and Fermt2 were also Alzheimer’s (AD) risk genes. In another study, Sadick and colleagues conducted a snRNA-seq on AD and non-symptomatic patients (NS) revealing heterogeneous astrocyte responses in AD. In their study, the authors defined global and subtype-specific transcriptomic changes between AD and NS astrocytes. Some of these patterns were related to astrocyte neuroprotective roles, while others indicated their contributions to neurodegenerative processes in AD. They further took advantage of recent human and mouse spatial transcriptomics resources to localize heterogeneous astrocyte subtypes to specific regions. Finally, they integrated their data with published AD snRNA-seq datasets, highlighting the power of combining datasets to resolve previously unidentifiable astrocyte subpopulations. Collectively, these findings enrich our comprehension of the role of astrocytes in both physiological conditions and within the context of AD. They also suggest the possibility that restoring astrocyte morphology in AD disease could potentially enhance neuronal and tissue support functions, making it a promising therapeutic avenue. Nevertheless, the question of how the heterogeneity in astrocyte responses may vary with disease progression or other patient cohort characteristics, such as sex or AD-associated mutations, remains open. Understanding this diversity in astrocyte responses during neurodegenerative processes is pivotal, as it lays the foundation for future efforts aimed at promoting the pro-reparative state and mitigating the detrimental ones.