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Are We Closer to Effective Treatment for AD?

By Laura Hall
April 2010

Anika Hartz, Ph.D.
"We are currently preparing for a long-term feeding study, where hAPP mice receive a PXR activating compound through their diet," said first author Hartz. "We will then look at their brains to see if long-term upregulation prevents onset and progression of AD." (Photo courtesy of Anika Hartz)

Bjoern Bauer, Ph.D.
"Besides the current $100 billion health care cost factor, AD is a devastating disease," said co-author Bjoern Bauer, Ph.D. (http://www.pharmacy.umn.edu/faculty/bauer_bjoern/home.html)Exit NIEHS, assistant professor at UMN. (Photo courtesy of Bjoern Bauer)

David Miller, Ph.D.
"Our paper shows how a basic understanding of three aspects of blood-brain barrier biology - transport protein function, its alteration in neurodegenerative disease, and mechanisms of transporter regulation - provides a new strategy to slow disease progression," said Miller. (Photo courtesy of Steve McCaw)

NIEHS Principal Investigator David Miller, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/ltp/intrareg/index.cfm), and two of his former NIEHS postdoctoral fellows now at the University of Minnesota (UMN) have demonstrated a treatment for mice with Alzheimer's Disease (AD) that reduces AD pathology. The same strategy could be effective in delaying onset and slowing the progression of AD in humans.

In the study (http://www.ncbi.nlm.nih.gov/pubmed/20101004?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1)Exit NIEHS, which was partially funded by NIEHS, the researchers established a protein called P-glycoprotein (P-gp) as one of the critical proteins involved in reducing amyloid beta (Aβ) accumulation in the brain. Aβ is the neurotoxic protein associated with AD that destroys brain nerve cells, or neurons. In their therapeutic strategy, the scientists targeted pregnane X receptor (PXR), a regulator of P-gp, increasing P-gp levels in brain blood vessels, which in turn decreased brain Aβ levels.

"Our experiments were done in young AD mice that do not yet have any cognitive impairment - technically, they are considered healthy," said first author Anika Hartz, Ph.D. (http://www.med.umn.edu/duluth/Faculty/Hartz_Anika/home.html)Exit NIEHS, research associate in the Medical School at UMN and a former member of Miller's group. "However, we found that their blood-brain barrier (BBB) biochemistry is already significantly changed."

AD causes neurons in the brain to die, resulting in progressive memory loss and the increasing inability to carry out daily functions. It is the most common form of dementia in older people, currently affecting up to 4.5 million people in the U.S. As the U.S. population ages, more people will be affected because the risk of AD doubles for every five-year age interval beyond age 65.

The Treatment

To see whether they could restore P-gp levels in the genetically engineered AD mice, known as hAPP mice (see text box), the scientists used PXR activation. PXR, a nuclear receptor, senses xenobiotic compounds, binds to these compounds called ligands, and then binds to DNA and controls the expression of drug metabolizing enzymes and certain transporters like P-gp. Upregulating these genes can help to eliminate foreign compounds from the body.

Treating the 12-week-old AD mice once a day for seven days with a PXR ligand increased P-gp amounts in brain capillary membranes and P-gp activity levels in capillaries to levels of those in normal control mice. Importantly, brain human Aβ accumulation in these treated hAPP mice was acutely reduced by up to 60 percent.

The authors said that P-gp transport of Aβ "may well be the limiting factor in Aβ brain clearance and one critical step that is defective in AD" and that lowered P-gp expression at the BBB is an "early biochemical manifestation of AD pathology that occurs before cognitive symptoms are evident." They added that increasing P-gp levels in the BBB during the early stages of AD by targeting signals that upregulate P-gp expression, like PXR, could be a new therapeutic strategy for AD.

Citation: Hartz AMS, Miller DS, Bauer B. (http://www.ncbi.nlm.nih.gov/pubmed/20101004?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1)Exit NIEHS 2010. Restoring blood-brain barrier P-glycoprotein reduces brain A{beta} in a mouse model of Alzheimer's disease. Mol Pharmacol. February 26, Doi:10.1124/mol.109.061754 [Epub ahead of print]

This research was supported in part by the National Institute of Environmental Health Sciences Intramural Research Program [Z01 ES080048].

(Laura Hall is a biologist in the NIEHS Laboratory of Pharmacology currently on detail as a writer for the Environmental Factor.)

Protein Transport and the Blood-Brain Barrier

The blood-brain barrier (BBB) separates the body's circulating blood from the fluid that bathes the brain's cells. The BBB protects the brain by limiting its exposure to substances in the blood. The major constituent of the BBB is the network of small blood vessels called capillaries that supply the brain cells with nutrients. The capillary walls are lined with endothelial cells.

P-gp Transports hAβ

Hartz and her colleagues isolated functioning brain capillaries - which closely mimic the BBB in vivo - from control mice and AD mice and performed experiments treating the capillaries themselves or the animals before the capillaries were removed. The AD model mice were transgenic, having a human gene that caused overexpression of the human amyloid precursor protein (hAPP). Enzymes cut hAPP in vivo to form human Aβ (hAβ).

The scientists showed that P-gp transported hAβ across the capillaries into the blood-space - the inside of the blood capillaries - that is, away from the brain. In untreated 12-week-old hAPP mice - which exhibit hAβ accumulation in the brain but show no sign of cognitive impairment - brain capillary P-gp protein level and activity was reduced by 70 percent compared to control mice. Other proteins known to move Aβ into the capillary cells did not contribute to this difference in hAβ transport.



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