Abstract
The intactness of blood–brain barrier (BBB) is compromised in Alzheimer’s disease (AD). Importantly, evidence suggests that the perturbation and abnormalities appearing in BBB can manifest early in the progression of the disease. The disruption of BBB allows extravasation of the plasma protein, fibrinogen, to enter brain parenchyma, eliciting immune reactivity and response. The presence of amyloid-β (Aβ) peptide leads to the formation of abnormal aggregates of fibrin resistant to degradation. Furthermore, Aβ deposits act on the contact system of blood coagulation, altering levels of thrombin, fibrin clots and neuroinflammation. The neurovascular unit (NVU) comprises an ensemble of brain cells which interact with infiltrating fibrinogen. In particular, interaction of resident immune cell microglia with fibrinogen, fibrin and Aβ results in the production of reactive oxygen species (ROS), a neurotoxic effector in AD brain. Overall, fibrinogen infiltration through a leaky BBB in AD animal models and in human AD tissue is associated with manifold abnormalities including persistent fibrin aggregation and clots, microglial-mediated production of ROS and diminished viability of neurons and synaptic connectivity. An objective of this review is to better understand how processes associated with BBB leakiness to fibrinogen link vascular pathology with neuronal and synaptic damage in AD.
Highlights
Considerable experimental evidence has linked abnormalities in BBB with the early and progressive loss of memory and cognitive function which characterize Alzheimer’s disease (AD) brain. One such abnormality is the leakage of fibrinogen into brain parenchyma and the subsequent effects of the plasma protein to activate cells comprising the neurovascular unit (NVU)
Perturbations in vascular function likely constitute a component of multifactorial abnormalities in AD pathology
The passage of plasma protein fibrinogen into brain is associated with a multiplicity and complexity of effects on cells of the NVU
Summary
Alzheimer’s disease (AD) is manifest as deficiencies in cognitive function and memory arising from abnormalities in neuronal and synaptic signaling in diseased brain [1]. A common finding from the different animal model studies was that infiltrating fibrin(ogen) showed evidence for co-localization with deposits of Aβ in brain parenchyma. The difficulties in the interpretation and translation of results from AD animal model studies to the human disease condition have recently been considered [17] In this regard, to help validate animal model data on fibrinogen entry through a damaged BBB, postmortem brain tissue from AD patients and control ND (non-demented) individuals has been examined. Human AD brain was characterized by leakiness of BBB, infiltration of fibrinogen into parenchyma and localization of the plasma protein in regions containing Aβ peptide. Aβ modulation of the activation of the factor XII-dependent contact system in microvessels and in brain parenchyma with leaky BBB could contribute to neuroinflammation and neurodegeneration in AD. Cells expressing receptors for their own secretory products can demonstrate an amplification of response within the NVU network
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