Alzheimers Amyloid Plaques May Originate in the Liver

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An estimated 5.1 million Americans have Alzheimer’s disease, including nearly half of people age 85 and older. Although the body produces amyloid precursor protein (APP) naturally, in a healthy brain, fragments called beta amyloid are broken down and eliminated. In the brains of patients with Alzheimer’s disease, they accumulate to form hard insoluble plaques that interrupt the signals between neurons.

Mouse Studies Find Genes for Amyloid Production, FDA-Approved Drug May Decrease Plaque Accumulation

Researchers from the Scripps Research Institute and ModGene LLC have unexpectedly discovered that the liver, and not the brain, is the source of the amyloid proteins that deposit as plaques.

Lead researcher Greg Sutcliffe and a team of scientists used a mouse model for Alzheimer’s disease to identify genes that influence the amount of amyloid that accumulates in the brain. They found three genes that protected mice from brain amyloid accumulation and deposition. For each gene, lower expression in the liver protected the mouse brain.

Read: Alzheimers Plaques Inhibit Compound Important for Brain Blood Flow

One of the genes encodes presenilin, a cell membrane protein. Dominant mutations in the genes that encode presenilin are the most common cause of familial early-onset Alzheimer’s disease. To form amyloid beta proteins, amyloid precursor protein (APP) must be cut by two enzymes, beta secretase and gamma secretase. Presenilin is the sub-component of gamma secretase.

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“Unexpectedly, heritable expression of Presenilin2 was found in the liver but not in the brain,” said Sutcliffe. “Higher expression of Presenilin2 in the liver correlated with greater accumulation of beta amyloid in the brain and development of Alzheimer’s-like pathology.”

“This unexpected finding holds promise for the development of new therapies to fight Alzheimer’s,” concluded Sutcliffe. If scientists can block production of beta amyloid in the liver, it could prevent the fragments from circulating in the blood and entering the brain.

Read: Vitamin D, Curcumin Clear Amyloid Plaques In Alzheimer's

The researchers tested an FDA-approved drug for cancer called imatinib (brand name Gleevec), a relatively new medication that reduces the production of beta amyloid in neuroblastoma cells transfected by amyloid precursor protein. Importantly, Gleevec has poor penetration of the blood-brain barrier in both mice and humans.

Mice were injected with imatinib twice a day for seven days. Plasma and brain tissue were collected and the amount of beta amyloid measured. The researchers found that the drug dramatically reduced beta amyloid in both the blood and the brain.

Sutcliffe says he hopes to find a partner and investors to move the work into clinical trials and new drug development.

Journal Reference:
"Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: Implications for Alzheimer's disease"
J. Gregor Sutcliffe, Peter B. Hedlund, Elizabeth A. Thomas, Floyd E. Bloom, Brian S. Hilbush
Journal of Neuroscience Research: 3 MAR 2011 DOI: 10.1002/jnr.22603

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