Summary Alzheimer's disease (AD) is a neurodegenerative disorder in which vascular pathology plays an important role. Since the β-amyloid peptide (Aβ) is a critical factor in this disease, we examined its relationship to fibrin clot formation in AD. In vitro and in vivo experiments showed that fibrin clots formed in the presence of Aβ are structurally abnormal and resistant to degradation. Fibrin(ogen) was observed in blood vessels positive for amyloid in mouse and human AD samples, and intravital brain imaging of clot formation and dissolution revealed abnormal thrombosis and fibrinolysis in AD mice. Moreover, depletion of fibrinogen lessened cerebral amyloid angiopathy pathology and reduced cognitive impairment in AD mice. These experiments suggest that one important contribution of Aβ to AD is via its effects on fibrin clots, implicating fibrin(ogen) as a potential critical factor in this disease.

Cerebrovascular dysfunction contributes to the pathology and progression of Alzheimer's disease (AD), but the mechanisms are not completely understood. Using transgenic mouse models of AD (TgCRND8, PDAPP, and Tg2576), we evaluated blood–brain barrier damage and the role of fibrin and fibrinolysis in the progression of amyloid-β pathology. These mouse models showed age-dependent fibrin deposition coincident with areas of blood–brain barrier permeability as demonstrated by Evans blue extravasation. Three lines of evidence suggest that fibrin contributes to the pathology. First, AD mice with only one functional plasminogen gene, and therefore with reduced fibrinolysis, have increased neurovascular damage relative to AD mice. Conversely, AD mice with only one functional fibrinogen gene have decreased blood–brain barrier damage. Second, treatment of AD mice with the plasmin inhibitor tranexamic acid aggravated pathology, whereas removal of fibrinogen from the circulation of AD mice with ancrod treatment attenuated measures of neuroinflammation and vascular pathology. Third, pretreatment with ancrod reduced the increased pathology from plasmin inhibition. These results suggest that fibrin is a mediator of inflammation and may impede the reparative process for neurovascular damage in AD. Fibrin and the mechanisms involved in its accumulation and clearance may present novel therapeutic targets in slowing the progression of AD.

The increase in blood flow evoked by synaptic activity is essential for normal brain function and underlies functional brain imaging signals. Nitric oxide, a vasodilator released by NMDA receptor activation, is critical for the flow increase, but the factors linking NMDA receptor activity to nitric oxide-dependent hyperemia are poorly understood. Here, we show that tissue plasminogen activator (tPA), a serine protease implicated in NMDA receptor signaling, is required for the flow increase evoked by somatosensory stimulation. tPA acts by facilitating neuronal nitric oxide release, but this effect does not involve enhancement of NMDA currents or the associated intracellular Ca 2؉ rise. Rather, the evidence suggests that tPA controls NMDA-dependent nitric oxide synthesis by influencing the phosphorylation state of neuronal nitric oxide synthase. These findings unveil a previously unrecognized role of tPA in vital homeostatic mechanisms coupling NMDA receptor signaling with nitric oxide synthesis and local cerebral perfusion.calcium ͉ cerebral blood flow ͉ mouse ͉ nitric oxide ͉ phosphorylation T issue plasminogen activator (tPA) is a serine protease best known for its role in intravascular fibrinolysis (1-3). tPA converts plasminogen (plg) into plasmin, a protease that cleaves fibrin and dissolves newly formed clots (2). The ''clot-busting'' properties of tPA have been used successfully in the treatment of myocardial infarction and ischemic stroke (4, 5). In addition to its role in fibrinolysis, tPA has recently emerged as a pleiotropic neuromodulator implicated in various aspects of brain function (6). tPA is stored in neurons and is released in an activity-dependent manner via exocytosis (7,8). tPA is involved in neurotransmission, synaptic plasticity, dendritic remodeling, and sympathetic nerve activity, effects related to its ability to influence NMDA receptor function, extracellular matrix integrity, and neurotransmitter release (9-15). In addition, tPA released from endothelial cells modulates cerebrovascular tone and may contribute to the hemodynamic changes induced by brain ischemia and trauma (3,(16)(17)(18).The vascular effects of tPA and its involvement in synaptic function raise the possibility that this protease also contributes to the neurovascular mechanisms linking brain activity to cerebral blood flow (CBF). The brain lacks energy reserves and its integrity depends on a continuous supply of oxygen and glucose through CBF (19). Because of such dependence on CBF, the brain is endowed with complex regulatory mechanisms that match local cerebral perfusion to the energy needs of active neurons on a moment-to-moment basis (19). Thus, an increase in regional brain activity is associated with a rapid and spatially focused increase in CBF, a response termed ''functional hyperemia' ' (19, 20). The close temporal and spatial correspondence between brain activity and CBF constitutes the basis of functional brain imaging techniques that use the local hemodynamic response evoked by neural activity to localize b...

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