Differential Responses of Human Astrocytes to Amyloid β1-42 Treatment: a comparative study between astrocytes from healthy individuals and Alzheimer’s patients

Aging is a complex biological phenomenon that represents the main risk factor for the development of age-related diseases, including Alzheimer's disease (AD). The formation of senile plaques, mainly formed by misfolded and assembled Aβ, seems to be one of the pathological features of AD. Among these, the small oligomeric forms of Aβ1-42 induce particularly toxic and neuroinflammatory effects. Astrocytes perform multiple functions in the central nervous system to maintain homeostasis and support neuronal function. Notably, age-related neurodegenerative disorders are often caused by the disruption of astrocytes’ normal physiological functions. Herein, we show in vitro the effects of Aβ1-42 oligomers on human primary astrocytes obtained from healthy subjects and AD patients, considering also gender differences. We demonstrated that astrocytes from all individuals can internalize Aβ1-42 oligomers, especially females. This internalization contributed to changing the proteasome activity and intracellular calcium levels. The treatment caused a reduction in cell viability by inducing apoptosis in astrocytes from healthy subjects, but not in those from AD patients. Indeed, Aβ-treatment induced a senescent state in astrocytes from AD patients and, among these particularly in females, as evidenced by the presence of relevant markers, such as increased senescence-associated β-galactosidase activity, p14ARF expression, and senescence-associated heterochromatin foci. Furthermore, the treatment of differentiated neuroblastoma cells, with conditioned media from treated astrocytes from healthy subjects and AD patients, showed that only those from AD-astrocytes induced cell death. These results highlight the close relationship between cellular senescence and Alzheimer's disease, suggesting its probable role in the pathogenesis and progression of the disease, especially in women.