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Although neuronal stress circuits have been identified, little is known about the mechanisms that underlie the stress-induced neuronal plasticity leading to fear and anxiety. Here we found that the serine protease tissue-plasminogen activator (tPA) was upregulated in the central and medial amygdala by acute restraint stress, where it promoted stress-related(More)
Repeated stress can impair function in the hippocampus, a brain structure essential for learning and memory. Although behavioral evidence suggests that severe stress triggers cognitive impairment, as seen in major depression or posttraumatic stress disorder, little is known about the molecular mediators of these functional deficits in the hippocampus. We(More)
Cerebrovascular amyloid beta-protein (A beta) deposition is a key pathological feature of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). A beta(1-40) containing the E22Q HCHWA-D mutation, but not wild-type A beta(1-40), potently induces several pathologic responses in cultured human cerebrovascular smooth(More)
Accumulation of the amyloid-beta (Abeta) peptide depends on both its generation and clearance. To better define clearance pathways, we have evaluated the role of the tissue plasminogen activator (tPA)-plasmin system in Abeta degradation in vivo. In two different mouse models of Alzheimer's disease, chronically elevated Abeta peptide in the brain correlates(More)
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-beta pathology. These mouse(More)
Although conventionally associated with fibrin clot degradation, recent work has uncovered new functions for the tissue plasminogen activator (tPA)/plasminogen cascade in central nervous system physiology and pathology. This extracellular proteolytic cascade has been shown to have roles in learning and memory, stress, neuronal degeneration, addiction and(More)
Cerebral amyloid angiopathy (CAA) due to amyloid beta-protein (Abeta) is a key pathological feature of patients with Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D). The CAA in these disorders is characterized by deposition of Abeta in the smooth muscle cells within the cerebral vessel wall. Recently, a new(More)
Chronic ethanol abuse causes up-regulation of NMDA receptors, which underlies seizures and brain damage upon ethanol withdrawal (EW). Here we show that tissue-plasminogen activator (tPA), a protease implicated in neuronal plasticity and seizures, is induced in the limbic system by chronic ethanol consumption, temporally coinciding with up-regulation of NMDA(More)
Alzheimer's disease (AD) is the leading cause of cognitive decline in aged individuals. The pathological hallmarks of AD include the formation of neurofibrillary tangles, along with senile plaques that are mainly composed of the amyloid-beta (Abeta) peptide. Several lines of evidence implicate the tPA/plasmin system in AD. One type of cell death observed in(More)
Microtubule associated protein tau is the major component of the neurofibrillary tangles (NFTs) found in the brains of patients with Alzheimer’s disease and several other neurodegenerative diseases. Tau mutations are associated with frontotemperal dementia with parkinsonism on chromosome 17 (FTDP-17). rTg4510 mice overexpress human tau carrying the P301L(More)