Objective: Intraventricular hemorrhage (IVH) is found in approximately 40% of intracerebral hemorrhages and is associated with increased mortality and poor functional outcome. Cognitive impairment is one of the complications and occurs due to various pathological changes. Amyloid beta (Aβ) accumulation and neuroinflammation, and the Alzheimer disease-like pathology, may contribute to cognitive impairment. Iron, the degradation product of hemoglobin, correlates with Aβ. In this study, the authors investigated the correlation between Aβ accumulation with enhanced neuroinflammation and cognitive impairment in a rat model of IVH.
Methods: Nine male Sprague-Dawley rats underwent an intraventricular injection of autologous blood. Another 9 rats served as controls. Cognitive function was assessed by the Morris water maze and T-maze rewarded alternation tests. Biomarkers of Aβ accumulation, neuroinflammation, and c-Jun N-terminal kinase (JNK) activation were examined.
Results: Cognitive function was impaired in the autologous blood injection group compared with the control group. In the blood injection group, Aβ accumulation was observed, with a co-located correlation between iron storage protein ferritin and Aβ. Beta-site amyloid precursor protein cleaving enzyme-1 (BACE1) activity was elevated. Microgliosis and astrogliosis were observed in hippocampal CA1, CA2, CA3, and dentate gyrus areas, with elevated proinflammatory cytokines tumor necrosis factor-α and interleukin-1. Protein levels of phosphorylated JNK were increased after blood injection.
Conclusions: Aβ accumulation and enhanced neuroinflammation have a role in cognitive impairment after IVH. A potential therapeutic method requires further investigation.
Keywords: AD = Alzheimer disease; APOE = apolipoprotein E; Aβ = amyloid beta; BACE1; BACE1 = beta-site amyloid precursor protein cleaving enzyme–1; DG = dentate gyrus; ELISA = enzyme-linked immunosorbent assay; GFAP = glial fibrillary acidic protein; IL-1 = interleukin-1; IVH = intraventricular hemorrhage; Iba1 = ionized calcium binding adapter molecule–1; JNK; JNK = c-Jun N-terminal kinase; MWM = Morris water maze; NeuN = neuron-specific nuclear protein; P-JNK = phosphorylated JNK; RFU = relative fluorescence units; T-JNK = total JNK;; TNFα = tumor necrosis factor–α; amyloid beta; beta-site amyloid precursor protein cleaving enzyme–1; c-Jun N-terminal kinase; ferritin; intraventricular hemorrhage; neuroinflammation; vascular disorders; βAPP = amyloid precursor protein beta.