Chronic Stress Exacerbates Cerebral Amyloid Angiopathy through Promoting NET formation [I]

Cerebral amyloid angiopathy (CAA) is the leading cause of vascular dementia among the elderly. Neuropsychiatric symptoms are commonly manifested in CAA patients but are usually considered as consequences of CAA pathology. Here, we report that chronic stress promotes CAA progression, which enhances deposition of amyloid protein beta (Aβ) in brain blood vessels and exacerbates subsequent brain injury. Mechanistically, neutrophil is implicated in CAA development. Aβ that accumulated in brain vasculature induces neutrophil extracellular traps (NETs) by activating STAT6 signaling, which inhibits neutrophil apoptosis and switches the programmed cell death toward NETosis. During chronic stress, circulatory Norepinephrine (NE) strengthens STAT6 activation in neutrophil and promotes NET formation, thus exacerbates the NET-dependent angiopathy. We demonstrate that inhibiting neutrophil chemotaxis towards brain or suppressing NET formation both ameliorate CAA severity in the context of chronic stress. Therefore, we propose that stress-associated psychological disorders and NETs are promising therapeutic targets in CAA. To investigate the underlying mechanism of Aß40-induced NETs, bone marrow derived neutrophils of mice were separated and treated with 20ug/ml Aß40 for 4h.