Alzheimer's Institute of America, Inc.

University of South Florida

Roskamp Research LLC

Elan Pharmaceuticals, Inc.

Imperial College of Science, Technology and Medicine

Roskamp Research Institute, LLC

Michael J Mullan

Daniel Paris

Jun Tan

Thomas Nadackal Thomas

Michael John Owen

Marie-Christine Chartier-Harlin

John Anthony Hardy

Robert A Ivey, Iii

Terrence C Town

Alison M Goate

Gary W Arendash

Terrence Town

Zhiming Suo

Fiona C Crawford

Alison Mary Goate

Robert A Iii Ivey

Robert A Ivey

The present invention provides methods for reducing A&#x3b2; deposition, A&#x3b2; neurotoxicity and microgliosis in an animal or human afflicted with a cerebral amyloidogenic disease, such as Alzheimer's disease (AD), by administering therapeutically effective amounts of the (R)-enantiomer of the dihydropyridine compound nilvadipine, also known as (&#x2212;)-nilvadipine, to the animal or human. Further provided are methods for reducing the risk of A&#x3b2; deposition, A&#x3b2; neurotoxicity and microgliosis in animals or humans suffering from traumatic brain injury by administering (&#x2212;)-nilvadipine after the traumatic brain injury and continuing treatment for a prescribed period of time thereafter.

Method for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis with (-)-nilvadipine enantiomer

Pharmaceutical compositions for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis

Provided are A&#x3b2; peptide fragments that are useful in inhibiting angiogenesis. Also provided are methods for the treatment of pathological or unwanted angiogenesis and conditions and diseases associated therewith by administering an effective amount of an A&#x3b2; fragment. In a particular embodiment, the peptide fragment includes the sequence HHQKLVFF.

Modulation of angiogenesis by A-beta peptide fragments

The present invention provides methods for reducing &#x3b2;-amyloid deposition, &#x3b2;-amyloid neurotoxicity and microgliosis in animals or humans afflicted with a cerebral amyloidogenic disease, such as Alzheimer's disease (AD), by administering therapeutically effective amounts of the dihydropyridine calcium channel antagonist, nilvadipine. The present invention also provides methods for diagnosing cerebral amyloidogenic diseases in animals or humans. Further provided are methods for reducing the risk of &#x3b2;-amyloid deposition, &#x3b2;-amyloid neurotoxicity and microgliosis in animals or humans suffering from traumatic brain injury by administering nilvadipine immediately after the traumatic brain injury and continuing treatment for a prescribed period of time thereafter. Finally, methods are provided for treating transplantable neuronal stem cells by administering nilvadipine to the neuronal stem cells prior to transplantation in the central nervous system of an animal or human afflicted with a cerebral amyloidogenic disease, such as AD.

Method for reducing amyloid deposition, amyloid neurotoxicity and microgliosis

There is provided a method of modifying vasoactivity by regulating a soluble A&#x3b2; pro-inflammatory pathway. Also provided is a method of modifying inflammatory reactions in microglia and neurons by regulating a soluble A&#x3b2; pro-inflammatory pathway. A method of treating patients with vascular disease by modifying an intracellular soluble A&#x3b2; pro-inflammatory pathway is also provided. A pharmaceutical composition consisting essentially of an effective amount of a soluble A&#x3b2; pro-inflammatory pathway regulator in a pharmaceutically effective carrier is also provided.

Modulation of the phospholipase A2 pathway as a therapeutic

The present invention provides methods and compositions for treating diseases and pathological conditions or processes mediated by undesired and/or uncontrolled angiogenesis (characterized as 'angiogenic diseases'), in particular cancer, by increasing the in vivo concentration of the A&#x3b2; peptide, within a patient suffering from such diseases, conditions or processes. The present invention also concerns diagnostic methods and kits for the detection and measurement of anti-angiogenic A&#x3b2; peptide activity in biological fluids and tissues. Such diagnostic methods and kits can be utilized to screen compounds for potential therapeutic activity in the treatment of angiogenic diseases such as Alzheimer's disease and cancer.

Inhibition of angiogenesis by A-&#x3b2; peptides

The invention provides an isolated nucleic acid characteristic of human amyloid precursor protein 770 including the nucleotides encoding codon 670 and 671, wherein the nucleic acid encodes an amino acid other than lysine at codon 670 and/or an amino acid other than methionine at codon 671. Also provided is a method of diagnosing or predicting a predisposition to Alzheimer's disease, comprising detecting in a sample from a subject the presence of a mutation at a nucleotide position corresponding to codons 670 and/or 671 of amyloid precursor protein or fragment thereof, the presence of the mutation indicating the presence of or a predisposition to Alzheimer's disease.

Transgenic mouse expressing an APP 670/671 mutation

Methods for assessing the risk of developing Alzheimer's Disease (AD), for diagnosing AD, and for measuring the progression of AD in a patient by determining CD45 isoform expression of blood cells obtained from the patient. The methods of the invention include determining CD45 isoform expression by cytometric analysis, quantitative Western immunoblotting, or quantitative RT-PCR or combinations thereof.

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Isolated cell comprising HAPP 670/671 DNAS sequences

There is provided an assay method for determining the effect of an agent on Alzheimer's Disease pathology by treating microglial cells with A&bgr; peptides, adding CD40 ligand to the microglial cells, adding a therapeutic agent to the microglial cells, and measuring Alzheimer's Disease pathology. Also provided is a method of determining therapeutic effectiveness of an agent for Alzheimer's Disease by measuring the inhibition of CD40-CD40L binding in the presence of the agent. An assay for determining the effect of an agent on Alzheimer's Disease pathology having A&bgr; peptides for adding to microglial cells, CD40 ligand for being added to the microglial cells, a therapeutic agent being added to the microglial cells and a measuring device for reassuring Alzheimer's Disease pathology is also provided.

Assay for evaluating the therapeutic effectiveness of agents in reducing Alzheimer's disease pathology

Model systems of Alzheimer's disease comprise a DNA sequence encoding an amyloid precursor protein (APP) isoform or fragment that has an amino acid substitution. The substituted amino acid may be other than valine at the amino acid position corresponding to amino acid residue position 717 of APP770. Methods of determining genetic predisposition to Alzheimer's disease are also disclosed.

Transgenic mouse expressing an APP-FAD DNA sequence

A method is disclosed for treating and preventing diseases, wherein at least one of the causes of the disease is .beta.-amyloid peptide induced change in free radical production resulting in vascular endothelial dysfunction and vasoactivity, by antagonizing vascular free radicals in excess of functional equilibrium.

Vasoactive effects and free radical generation by .beta.-amyloid peptides

A method is disclosed for treating and preventing diseases, wherein at least one of the causes of the disease is .beta.-amyloid peptide induced change in free radical production resulting in vascular endothelial dysfunction and vasoactivity, by antagonizing vascular free radicals in excess of functional equilibrium. An animal model for the disease is also disclosed.

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Tampa, FL, United States of America

Michael J Mullan