Methods for decreasing beta amyloid protein

a beta amyloid and protein technology, applied in the field of methods for decreasing beta amyloid protein, can solve the problems of high toxicity of a protein to nerve cells, and achieve the effects of reducing blood cholesterol, reducing the risk of developing ad, and reducing the production of a

Inactive Publication Date: 2006-02-02
CHILDRENS MEDICAL CENT CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007] Blood cholesterol levels are correlated with production of amyloid β protein (Aβ), and are predictors of populations at risk of developing AD. Methods for lowering blood cholesterol levels can be used to decrease production of Aβ, thereby decreasing the risk of developing AD. The same methods and compositions can also be used for treating individuals diagnosed with AD. Methods include administration of compounds which increase uptake of cholesterol by the liver, such as the administration of HMG CoA reductase inhibitors, administration of compounds which block endogenous cholesterol production, such as administration of HMG CoA reductase inhibitors, administration of compositions which prevent uptake of dietary cholesterol, and administration of combinations of any of these which are effective to lower blood cholesterol levels. Methods have also been developed to predict populations at risk, based on the role of cholesterol in production of Aβ. For example, individuals with Apo E4 and high cholesterol, defined as a blood cholesterol level of greater than 200 mg / dl, post menopausal women with high cholesterol levels—especially those who are not taking estrogen, or individuals which high blood cholesterol levels who are not obese are all at risk of developing AD if blood cholesterol levels are not decreased. In the preferred embodiment, individuals with these risk factors are treated to lower blood cholesterol levels prior to developing any mental impairment attributable to AD, based on accepted neuropsychiatric and diagnostic criteria in clinical practice. Treatment is based on adminstration of one or more compositions effective to lower cholesterol blood levels at least 10%, which is believed to be sufficient to decrease production of Aβ.

Problems solved by technology

Finally, the Aβ protein has been demonstrated to be highly toxic to nerve cells.

Method used

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Examples

Experimental program
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Effect test

example 1

Cholesterol Increases the Level of Aβ in Human Neuronial Cultures

[0027] Busciglio et al., (1993) Proc. Nat. Acad. Sci. 90, 2092-2096, described the production of Aβ by human cortical neurons in culture . To determine whether cholesterol can affect the production of Aβ, primary human brain cultures were established from the cortex of 16-20 week fetal abortuses, and the neurons incubated in the absence or presence of very low density lipoprotein (VLDL), low density lipoprotein (LDL) or high density lipoprotein (HDL) particles isolated from human plasma. These lipoprotein particles are the physiological vehicles for the transport of cholesterol to cells. The effects of the different lipoprotein particles on the levels of Aβ in the human cortical cultures was determined. The human cortical cultures were maintained in serum-free Dulbecco's Modified Eagle's Medium (DMEM) with N2 supplements (a serum-free supplement that supports neuronal viability). The medium was then changed to the sam...

example 2

Dietary Cholesterol Increases Aβ Levels in the Brain

[0030] After establishing that cholesterol-carrying lipoprotein particles increase Aβ in cultures of human neurons, it was determined whether dietary cholesterol increases the level of Aβ in the brain in vivo. Increased dietary intake of cholesterol is known to increase circulating levels of lipoprotein particles, which in turn increases the delivery of cholesterol to cells. These experiments were performed on 20 month old rats. The rats were fed a low cholesterol diet (0.1% cholesterol) or a high cholesterol diet (5% cholesterol). After 10 weeks, the animals were sacrificed and the cortex was removed for measurement of Aβ levels. Aβ was assayed by immunoprecipitating cortical homogenates with the Aβ antibody B12, followed by Western blotting with the commercially available Aβ monoclonal antibody 4G8.

[0031] Resolution of the Aβ isolated from rat cerebral cortex by electrophoretic separation on gels showed that Aβ levels were sign...

example 3

HMG CoA Reductase Inhibitors Inhibit the Production of Aβ by Human Neurons

[0032] The HMG CoA reductase inhibitors have been used in humans to decrease plasma levels of cholesterol in patients at risk for heart disease. The discovery that cholesterol increases the amount of Aβ in the brain led to this investigation to determine whether the HMG CoA reductase inhibitors may be therapeutically efficacious for Alzheimer's disease by inhibiting the production of Aβ. Human cortical neuronal cultures were established from 18 weeks gestation normal fetal cortical tissue as described above and maintained in a culture medium comprised of DMEM containing N2 supplements. After one week, the culture medium was changed to DMEM+N2 supplements (control), or DMEM+N2 supplements+either 100 μM lovastatin, 100 μM simvastatin, 100 μM compactin, 100 μM fluvastatin, or 1 mM pravastatin. after incubation for 48 hours, the cultured cells were harvested and the levels of Aβ were assayed, as described above. ...

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Abstract

Blood cholesterol levels are correlated with production of amyloid β protein (Aβ), and are predictors of populations at risk of developing AD. Methods for lowering blood cholesterol levels can be used to decrease production of Aβ, thereby decreasing the risk of developing AD. The same methods and compositions can also be used for treating individuals diagnosed with AD. Methods include administration of compounds which increase uptake of cholesterol by the liver, such as the administration of HMG CoA reductase inhibitors, administration of compounds which block endogenous cholesterol production, such as administration of HMG CoA reductase inhibitors, administration of compositions which prevent uptake of dietary cholesterol, and administration of combinations of any of these which are effective to lower blood cholesterol levels. Methods have also been developed to predict populations at risk, based on the role of cholesterol in production of Aβ. For example, individuals with Apo E4 and high cholesterol, defined as a blood cholesterol level of greater than 200 mg/dl, post menopausal women with high cholesterol levels—especially those who are not taking estrogen, or individuals which high blood cholesterol levels who are not obese are all at risk of developing AD if blood cholesterol levels are not decreased.

Description

[0001] The United States government has certain rights in this invention by virtue of National Institutes of Health grant number RO1NS33325 to Bruce A. Yankner.BACKGROUND OF THE INVENTION [0002] Alzheimer's disease (AD) is the most common cause of dementia in the aged population. The accumulation of large numbers of senile plaques containing the 40-42 amino acid amyloid β protein (Aβ) is a classic pathological feature of AD. Both genetic and cell biological findings suggest that the accumulation of Aβ in the brain is the likely cause of AD (Yankner, B. A. (1996) Neuron 16, 921-932; Selkoe, D. J. Science 275, 630-631 (1997)). Strong genetic evidence in support of the pathogenic role of Aβ came from the observation that individuals who inherit mutations in the amyloid precursor protein almost invariably develop AD at an early age. These mutations increase the production of a long variant of tile Aβ peptide that forms senile plaques in the brain (Goate et al., (1991) Nature 349, 704-70...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/401A61K31/366A61K31/225G01N33/92A61K31/00A61K31/22A61K31/365A61K31/40A61K31/404A61K31/44A61K31/4418A61K31/445A61K36/896A61K45/00A61P3/06A61P25/28A61P43/00G01N33/68
CPCA61K31/00A61K31/22A61K31/225A61K31/365A61K31/366A61K31/40G01N2800/2821A61K31/404A61K31/4418A61K31/445G01N33/6896G01N2333/4709A61K31/401A61P3/06A61P25/28A61P43/00
Inventor YANKNER, BRUCE A.NADEAU, PHILIP
Owner CHILDRENS MEDICAL CENT CORP
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