Enhanced oxidative stress contributes to worse prognosis and delayed neurofunctional recovery after striatal intracerebral hemorrhage in 5XFAD mice

• Published in: The European journal of neuroscience 2020-04, Vol.51 (8), p.1806-1814
• Main Authors: Hayashi, Kenyu, Hasegawa, Yu, Takemoto, Yushin, Cao, Cheng, Mukasa, Akitake, Kim‐Mitsuyama, Shokei
• Format: Article
• Language: English
• Subjects: 5XFAD; Acute effects; Alzheimer's disease; Amyloid; Cerebral amyloid angiopathy; Cognitive ability; Collagen; Collagenase; Cytotoxicity; Edema; Hemorrhage; Hypertension; Long-term effects; Macrophages; Morbidity; Mortality; Neostriatum; Neurodegenerative diseases; Oxidative stress; Prognosis; striatal intracerebral hemorrhage
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.14596

Although Alzheimer's disease (AD) is associated with an increased risk of intracerebral hemorrhage (ICH) caused by hypertension and cerebral amyloid angiopathy, the precise clinical course after hypertensive ICH in AD patients is still unknown. In this study, we investigated how striatal ICH, a frequent site for hypertensive ICH, affected the prognosis of AD. We employed 17‐ and 18‐month‐old male 5XFAD (5X) mice and littermate (LT) controls, and striatal ICH was induced by collagenase injection. First, to address the acute effects of ICH on 5X mice, hemorrhagic volume and brain edema were evaluated 3 days after ICH. Next, to address the long‐term effects of ICH on 5X mice, morbidity, mortality, neurological function (beam‐walking and rotarod tests), and cognitive function (Y‐maze and nest‐building tests) were monitored. Twenty‐eight days later, the animals were euthanized, their brains were isolated, and the cytotoxic alterations were investigated. The results revealed that the acute effects of ICH were not significantly different between 5X and LT mice. In contrast, 5X mice showed significantly higher morbidity and mortality in response to ICH, as well as delayed neurological function recovery, compared to LT mice through 28 days. ICH did not affect cognitive function in either group. Infiltrated macrophages in the perihemorrhagic cortex, gp91phox, p67phox, and COX‐2 were significantly increased in 5X mice in response to ICH. We demonstrated that striatal ICH deteriorated prognosis and delayed neurofunctional recovery in 5X mice, which might be associated with enhanced oxidative stress in the presence of AD‐like pathology. We explored how intracerebral hemorrhage (ICH) affected the prognosis of 5XFAD mice. Striatal ICH worsened prognosis and delayed neurofunctional recovery in the mice, and infiltrated macrophages in peri‐hemorrhagic cortex and oxidative stress related proteins were increased at 28 days after ICH. The study suggest that additive oxidative stress in the presence of AD‐like pathology is induced by ICH and primarily associated with poor prognosis in 5XFAD mice.