METHODS FOR DIAGNOSING AND TREATING ALZHEIMER'S DISEASE BY ADMINISTERING AN ANTI-ANGIOGENIC AGENT
Methods for diagnosing and treating Alzheimer's disease are provided. In particular, methods of restoring blood-brain barrier integrity and/or promoting vascular reversion in a person suffering from Alzheimer's disease by administering an anti-angiogenic agent or an agent that is capable of restoring tight junction integrity. Methods of preventing or delaying the onset of Alzheimer's disease in a subject are also provided.
1 . A method of treating or delaying the onset of Alzheimer's disease in a patient having or at risk of developing Alzheimer's disease comprising administering to the subject an effective amount of an anti-angiogenic agent.
2 . A method of maintaining and/or restoring blood-brain barrier (BBB) integrity in a subject having or at risk of developing Alzheimer's disease comprising administering to the subject an effective amount of an anti-angiogenic agent and/or an agent that inhibits abeta amyloidogenesis or promotes removal of abeta peptide from the brain.
3 . A method of promoting vascular reversion in the brain of a subject having or at risk of developing Alzheimer's disease comprising administering to the subject an effective amount of an anti-angiogenic agent and/or an agent that promotes the removal of abeta peptide from the brain.
4 . The method of claim 1 , 2 or 3 , wherein the anti-angiogenic agent is bexarotene, bevacizumab (Avastin®), imatinib, sorafenib, sunitinib, leflunomide (SU101), midostaurin (PKC412), vatalinib (PTK787/LK222584), AG013736, AZD2171, CP547,632, CP673,451, RPI.4610, VEGF Trap, ZD6474, YM359445, SU5416, temsirolimus (Toriser), batimastat, marimastat, neovastat, prinomastat, carboxyamidotriazole, TNP-470, CM101, IFN-□, IL-12, platelet factor-4, suramin, SU5416, thrombospondin, angiostatin, endostatin, thalidomide, tetrathiomolybdate, tecogalan, razoxane or reservatrol.
5 . The method of claim 3 , wherein the agent that promotes the removal of abeta peptide from the brain is abeta peptide, or an antibody that specifically binds abeta peptide.
6 . A method for identifying subjects at risk of developing Alzheimer's disease, or having early stage Alzheimer's disease, comprising detecting neoangiogenesis, TJ disruption and/or blood-brain barrier disruption in the brain of a subject.
7 . A method of identifying potential therapeutic agents for the treatment of Alzheimer's disease comprising testing the ability of a candidate agent to restore tight junctions in cerebral blood vessels or to promote vascular reversion in the brain.
8 . The method according to claim 7 , comprising the steps of:
providing a culture of a cell line that forms functional in vitro model of the blood-brain barrier,
contacting the culture with an agent that disrupts tight junctions,
contacting the culture with the candidate agent,
assessing integrity of the tight junctions in the cell culture
wherein an increase in integrity in the tight junctions compared to a control animal not receiving the candidate agent indicates the agent is a potential therapeutic agent.
9 . The method according to claim 7 , comprising the steps of:
administering the candidate agent to an animal model to Alzheimer's disease, and
assessing integrity of the tight junctions in the cerebral blood vessels,
wherein an increase in integrity in the tight junctions compared to a control animal not receiving the candidate agent indicates the agent is a potential therapeutic agent.