Increased Cerebrovascular Protein Transcytosis and Amyloid‐β Deposition during Hyperfibrinogenemia Alter Short‐term Memory

Many inflammatory and cognitive disorders including g Alzheimer's disease are accompanied by elevated blood level of fibrinogen (Fg), called hyperfibrinogenemia (HFg). Previously we showed that HFg increases microvascular permeability mainly affecting the transcellular transport pathway. In the present study, we tested the hypothesis that HFg increases cerebrovascular protein crossing via caveolar transcytosis leading to an increased formation of Fg and amyloid‐β (Aβ) complex, which results in loss of short‐term memory. Changes in cerebrovascular permeability were assessed in male wild type (WT, C57BL/6J) and transgenic HFg mice using a dual‐tracer probing method. In addition, in HFg mice brain vascular protein transcytosis was assessed in the presence or absence of in vivo siRNA against Caveolin‐1, which was encapsulated in liposomes that fuse with endothelium and was delivered systemically. Formation of Fg‐Aβ plaque was assessed in mouse brain cryo‐sections by immunohistochemistry. Short‐term memory of mice was estimated by a novel object recognition test (NORT). Results indicate that increased cerebrovascular protein leakage occurs mainly through caveolar transcytosis during HFg and it is greater than what is observed in control mice. Formation of Fg‐Aβ complex was increased in HFg mice compared to that in WT animals. NORT assessment demonstrated that HFg intensifies the loss of short‐term memory in mice. In conclusion, HFg increases cerebrovascular permeability and enhances Fg‐Aβ complex formation, which intensify short‐term memory loss and suggests a functional role of Fg in vasculo‐neuronal pathology.