Abstract: Pericytes are mural cells of brain capillaries that degenerate in multiple neurological disorders. Pericytes regulate neurovascular functions, but their role in the adult brain and disease is still poorly understood because of the lack of adequate pericyte-specific experimental models. All current pericyte-deficient models are not pericyte specific, and carry an inherited embryonic trait. Here, the Inventors generated an inducible pericyte-specific Cre line using a double-promoter strategy. The Inventors ablated adult mouse pericytes expressing Cre-dependent diphtheria toxin receptor after toxin administration. Pericyte ablation led to a rapid dysregulation of cerebral blood flow and blood-brain barrier breakdown. This was followed by behavioral deficits and neurodegenerative changes. These findings show that circulatory deficits leading to secondary neurodegeneration develop immediately after pericyte loss.

Abstract: Pericytes are mural cells of brain capillaries that degenerate in multiple neurological disorders. Pericytes regulate neurovascular functions, but their role in the adult brain and disease is still poorly understood because of the lack of adequate pericyte-specific experimental models. All current pericyte-deficient models are not pericyte specific, and carry an inherited embryonic trait. Here, the Inventors generated an inducible pericyte-specific Cre line using a double-promoter strategy. The Inventors ablated adult mouse pericytes expressing Cre-dependent diphtheria toxin receptor after toxin administration. Pericyte ablation led to a rapid dysregulation of cerebral blood flow and blood-brain barrier breakdown. This was followed by behavioral deficits and neurodegenerative changes. These findings show that circulatory deficits leading to secondary neurodegeneration develop immediately after pericyte loss.

Abstract: Activated protein C (APC), prodrug, and/or a variant thereof may be used as an inhibitor of apoptosis or cell death and/or a cell survival factor, especially for stressed or injured cells or tissues of the nervous system including subjects with neurode-generative disorders. Novel biological functions (e.g., neuroprotection) can be independent or separated from inhibition of clotting or inflammation, and other biological properties of APC (e.g., antithrombotic activity, ability to reduce NF?B-regulated gene expression). It can be used in the treatment of disease or other pathological conditions by at least inhibiting the p53-dependent and/or caspase-3-dependent pro-apoptotic signaling pathways in stressed or injured cells. Thus, APC, prodrugs, and variants thereof (e.g., APC protease domain mutants with reduced anti-coagulant activity) are prototypes of a class of agents for preventing apoptosis or cell death and/or promoting cell survival by direct action on brain cells.

Abstract: A soluble derivative of low-density lipoprotein receptor related protein-1 (sLRP-1) binds directly to Alzheimer's amyloid-? peptide (A?). This binding may be used to detect A? or to separate A? from the rest of a subject's body. In Alzheimer's disease, it may be used to provide diagnostic results by detecting A?, treatment by removing A?, or both.

Abstract: Protein S is a significant neuroprotectant when administered after focal ischemic stroke and prevents hypoxic/re-oxygenation injury. Purified human plasma-derived or recombinant protein S improves motor neurological function after stroke, and reduced brain infarction and edema. Protein S also enhances post-ischemic reperfusion and reduced brain fibrin and neutrophil deposition. Cortical neurons are protected from hypoxia/re-oxygenation-induced apoptosis. Thus, protein S and variants thereof are prototypes of a class of agents for preventing injury of the nervous system. In particular, a disease or other pathological condition (e.g., stroke) may be treated with such agents having one or more protein S activities (e.g., anti-thrombotic and anti-inflammatory activities, direct cellular neuronal protective effects) although the latter activities are not be required.

Abstract: Brain endothelial low-density lipoprotein receptor related protein-1 (LRP-1) mediates vascular clearance of Alzheimer's amyloid-? peptide (A?) from the brain. Transport of A? occurs across the blood-brain barrier (BBB) to the systemic circulation, but the brain endothelium is compromised in Alzheimer's disease. The invention is used to diagnose the disease in symptomatic and asymptomatic individuals, to identify those at risk for disease or already affected thereby, to determine the stage of disease or its progression, to intervene earlier in or alter the disease's natural history, to provide a target for therapeutic or prophylactic treatments, to screen drugs or compare medical regimens, to determine the effectiveness of a drug or medical regimen, or any combination thereof.

Abstract: Dysregulation of vascular function is observed in brain endothelium derived from patients affected by Alzheimer's disease. This may be manifested at the cell or organ level: e.g., abnormal capillary morphogenesis, defective angiogenesis, inappropriate cellular senescence, mitotic catastrophe, or combinations thereof. This observation can be used for diagnosis or treatment of neurodegenerative disorders and other cognitive impairments.

Abstract: The present invention provides a method for decreasing cerebral vasoconstriction in a subject suffering from chronic or acute cerebral amyloid angiopathy which comprises administering to the subject an inhibitor of receptor for advanced glycation endproduct (RAGE) in an effective amount to inhibit transcytosis of amyloid &bgr; peptides across the blood-brain barrier in the subject, thereby decreasing cerebral vasoconstriction in the subject. The invention further provides for a method for ameliorating neurovascular stress in a subject which comprises administering to the subject an effective amount of an inhibitor of receptor for advanced glycation endproduct (RAGE), so as to increase cerebral blood flow in the subject, thereby ameliorating neurovascular stress in the subject.

Abstract: The present invention provides a method for decreasing cerebral vasoconstriction in a subject suffering from chronic or acute cerebral amyloid angiopathy which comprises administering to the subject an inhibitor of receptor for advanced glycation endproduct (RAGE) in an effective amount to inhibit transcytosis of amyloid &bgr; peptides across the blood-brain barrier in the subject, thereby decreasing cerebral vasoconstriction in the subject. The invention further provides for a method for ameliorating neurovascular stress in a subject which comprises administering to the subject an effective amount of an inhibitor of receptor for advanced glycation endproduct (RAGE), so as to increase cerebral blood flow in the subject, thereby ameliorating neurovascular stress in the subject.

Abstract: The present invention provides a method for decreasing cerebral vasoconstriction in a subject suffering from chronic or acute cerebral amyloid angiopathy which comprises administering to the subject an inhibitor of receptor for advanced glycation endproduct (RAGE) in an effective amount to inhibit transcytosis of amyloid &bgr; peptides across the blood-brain barrier in the subject, thereby decreasing cerebral vasoconstriction in the subject. The invention further provides for a method for ameliorating neurovascular stress in a subject which comprises administering to the subject an effective amount of an inhibitor of receptor for advanced glycation endproduct (RAGE), so as to increase cerebral blood flow in the subject, thereby ameliorating neurovascular stress in the subject.