Promising Alzheimer's 'Drug' Halts Memory Loss

A new class of experimental drug-like small molecules is showing great promise in targeting a brain enzyme to prevent early memory loss in Alzheimer's disease, according to Northwestern Medicine® research.
Developed in the laboratory of D. Martin Watterson, the molecules halted memory loss and fixed damaged communication among brain cells in a mouse model of Alzheimer's.
"This is the starting point for the development of a new class of drugs," said Watterson, lead author of a paper on the study and the John G. Searle Professor of Molecular Biology and Biochemistry at Northwestern University Feinberg School of Medicine. "It's possible someday this class of drugs could be given early on to people to arrest certain aspects of Alzheimer's."
Changes in the brain start to occur ten to 15 years before serious memory problems become apparent in Alzheimer's.
"This class of drugs could be beneficial when the nerve cells are just beginning to become impaired," said Linda Van Eldik, a senior author of the paper and director of the University of Kentucky Sanders-Brown Center on Aging.

The novel drug-like molecule, called MW108, reduces the activity of an enzyme that is over-activated during Alzheimer's and is considered a contributor to brain inflammation and impaired neuron function. Strong communication between neurons in the brain is an essential process for memory formation.
"I'm not aware of any other drug that has this effect on the central nervous system," Watterson said.
"These exciting results provide new hope for developing drugs against an important molecular target in the brain," said Roderick Corriveau, program director at the National Institute of Neurological Disorders and Stroke, which helped support the research. "They also provide a promising strategy for identifying small molecule drugs designed to treat Alzheimer's disease and other neurological disorders."
Watterson and his collaborators have a new National Institutes of Health (NIH) award to further refine the compound so it is metabolically stable and safe for use in humans and develop it to the point of starting a phase 1 clinical trial.
In a key memory experiment in the study, mice brains were injected with beta-amyloid, whose increase is one hallmark of Alzheimer's in humans. One group of mice was then administered MW108 and another group was administered a placebo.
Next, each group of mice was taught environmental cues to learn how to swim through a water maze to find a resting platform. Then the mice were placed in a different arm of the maze and tested on their ability to remember the location of the platform based on the environmental cues.
The mice administered MW108 found the resting platform in the water maze as quickly as a control group of mice. The mice given the placebo made more mistakes and took longer to find the platform. They also had difficulty learning the location of the resting platform during the teaching phase.
"The results show the compound prevented the cognitive impairment," Van Eldik said..

Steroids might slow Alzheimer’s disease progression

Anti-inflammatory drugs for treatment and prevention of Alzheimer’s disease have to date proved disappointing, including a large study of low-dose prednisone, but higher dose of anabolic steroids significantly reduced amyloid secretion in a small series of nondemented patients. In addition, there is a case report of a patient with amyloid angiopathy who had complete remission from two doses of dexamethasone, and very high dose steroids are already used for systemic amyloidosis. This paper presents the hypothesis that pulse-dosed intrathecal methylprednisolone or dexamethasone will produce detectable slowing of Alzheimer’s progression, additive to that obtained with cholinesterase inhibitors and memantine. 

A protocol based on treatment regimens for multiple sclerosis and central nervous system lupus is outlined, to serve as a basis for formulating clinical trials. Ultimately intrathecal corticosteroids might become part of a multi-agent regimen for Alzheimer’s disease and also have application for other neurodegenerative disorders.

Gene May Protect Against Alzheimer’s Disease

New research has identified a genetic mutation that may protect against both Alzheimer's disease and age-related declines in thinking and memory. And future drug treatments already in the pipeline may help prevent against both.

Amyloid protein plaques in the brain are seen in people with Alzheimer's disease. A gene for amyloid-beta precursor protein (APP) plays a key role in the formation of these plaques. Researchers from Reykjavik, Iceland, found that a mutation in this gene may help protect against Alzheimer's disease and age-related mental decline.

This mutation is rare, but, when present, confers about a 40% reduction in amyloid plaque-forming proteins. What's more, study participants between 80 to 100 years old without Alzheimer's disease who carry this mutation have better mental function than those without the mutation, the study shows.

Alzheimer's disease affects memory and thinking. Symptoms usually develop slowly and worsen with time. One in eight older Americans has Alzheimer's disease, making it the most common type of dementia in the U.S., according to the Alzheimer's Association.

New Chemical Approach to Treat Alzheimer's

Scientists developed a new chemical approach to help harness the natural ability of complex sugars to treat Alzheimer's disease.

The team used a new chemical method to produce a library of sugars, called heparan sulphates, which are known to control the formation of the proteins in the brain that cause memory loss.

Heparan sulphates are found in nearly every cell of the body, and are similar to the natural blood-thinning drug, heparin. Now scientists have discovered how to produce them chemically in the lab, and found that some of these sugars can inhibit an enzyme that creates small proteins in the brain.

These proteins, called amyloid, disrupt the normal function of cells leading to the progressive memory loss that is characteristic of Alzheimer's disease.

There are more than 800,000 people in the UK, and 50,000 in New Zealand living with dementia. Over half of these have Alzheimer's disease, the most common cause of dementia. The cost of these diseases to the UK economy stands at £23 billion, more than the cost of cancer and heart disease combined. Current treatments for dementia can help with symptoms, but there are no drugs available that can slow or stop the underlying disease.

Preventing 'Traffic Jams' in Brain Cells

What you would see is a network of nerve cells called neurons, each with its own internal highway system for transporting essential materials between different parts of the cell.
When this biological machinery is operating smoothly, tiny motor proteins ferry precious cargo up and down each neuron along thread-like roadways called microtubule tracks. Brain cells are able to receive information, make internal repairs and send instructions to the body, telling the fingers to flex or the toes to curl.
But when the neuron gets blocked, this delicate harmony deteriorates. One result: diseases like Alzheimer's.

Understanding such blockages and how traffic should flow normally in healthy brain cells could offer hope to people with neurodegenerative diseases. Toward that end, a research team led by University at Buffalo biologist Shermali Gunawardena, PhD, has shown that the protein presenilin plays an important role in controlling neuronal traffic on microtubule highways, a novel function that previously was unknown.

Inside the nerves of fruit fly larvae, presenilin helped to control the speed at which molecular motors called kinesins and dyneins moved along neurons. When the scientists halved the amount of presenilin present in the highway system, the motors moved faster; they paused fewer times and their pauses were shorter.
Given this data, Gunawardena thinks that tweaking presenilin levels may be one way to free up traffic and prevent dangerous neuronal blockages in patients with Alzheimer's disease.


Presenilin rides along neuronal highways in tiny organic bubbles called vesicles that sit atop the kinesin and dynein motors, and also contain a second protein called the amyloid precursor protein (APP). Presenilin participates in cutting APP into pieces called amyloid beta, which build up to form amyloid plaques in patients with Alzheimer's disease.
Such buildups can lead to cell death by preventing the transport of essential materials -- like proteins needed for cell repair -- along neurons.
The findings of the new study mean that presenilin may contribute to Alzheimer's disease in at least two ways: not just by cleaving APP, but also by regulating the speed of the molecular motors that carry APP along neuronal highways.

Sleep Apnea Linked to Alzheimer's

But this latest study also poses an interesting question: Could AD in its "preclinical stages" also lead to SDB and explain the increased prevalence of SDB in the elderly?
The study will be presented at the ATS 2013 International Conference.

"It's really a chicken and egg story," said Ricardo S. Osorio, MD, a research assistant professor at NYU School of Medicine who led the study. "Our study did not determine the direction of the causality, and, in fact, didn't uncover a significant association between the two, until we broke out the data on lean and obese patients."

When the researchers did consider body mass, they found that lean patientswith SDB did possess several specific and non-specific biomarkers of AD risk. Among obese patients , glucose hypometabolism was also found in the medial temporal lobe, but was not significant in other AD-vulnerable regions.
"We know that about 10 to 20 percent of middle-aged adults in the United States have SDB [defined as an apnea-hypopnea index greater than 5] and that the number jumps dramatically in those over the age of 65," said Dr. Osorio, noting that studies put the percentage of people over the age of 65 with SDB between 30 and 60 percent. "We don't know why it becomes so prevalent, but one factor may be that some of these patients are in the earliest preclinical stages of AD."

According to Dr. Osorio, the biochemical harbingers of AD are present 15 to 20 years before any of its currently recognized symptoms become apparent.

The NYU study enrolled 68 cognitively normal elderly patients (mean age 71.4±5.6, range 64-87) who underwent two nights of home monitoring for SDB and were tested for at least one diagnostic indicator of AD. The researchers looked at P-Tau, T-Tau and Aβ42 in CSF, FDG-PET (to measure glucose metabolism), Pittsburgh compound B (PiB) PET to measure amyloid load, and/or structural MRI to measure hippocampal volume. Reduced glucose metabolism in AD-vulnerable regions, decreased hippocampal volume, changes in P-Tau, T-Tau and Aβ42, and increased binding of PiB-PET are recognized as markers of risk for AD and have been reported to be abnormal in healthy subjects before the disease onset.
Biomarkers for AD risk were found only among lean study participants with SDB. These patients showed a linear association between the severity of SDB and CSF levels of the biomarker P-Tau and between SDB and glucose hypometabolism using FDG-PET, in the medial temporal lobe, the posterior cingulate cortex/precuneus and a composite score of all AD-vulnerable regions . Lean SDB patients also showed smaller hippocampi when compared to lean controls, but no differences were found in measures of amyloid burden such as decreased Aβ42 in CSF or PiB positive scans.

Turning Alzheimer's Fuzzy Signals Into High Definition

Scientists at the Virginia Tech Carilion Research Institute have discovered how the predominant class of Alzheimer's pharmaceuticals might sharpen the brain's performance

One factor even more important than the size of a television screen is the quality of the signal it displays. Having a life-sized projection of Harry Potter dodging a Bludger in a Quidditch match is of little use if the details are lost to pixilation.

The importance of transmitting clear signals, however, is not relegated to the airwaves. The same creed applies to the electrical impulses navigating a human brain. Now, new research has shown that one of the few drugs approved for the treatment of Alzheimer's disease helps patients by clearing up the signals coming in from the outside world.The discovery was made by a team of researchers led by Rosalyn Moran, an assistant professor at the Virginia Tech Carilion Research Institute. Her study indicates that cholinesterase inhibitors -- a class of drugs that stop the breakdown of the neurotransmitter acetylcholine -- allow signals to enter the brain with more precision and less background noise.

Alzheimer's disease affects more than 35 million people worldwide -- a number expected to double every 20 years, leading to more than 115 million cases by 2050. Of the five pharmaceuticals approved to treat the disease by the U.S. Food and Drug Administration, four are cholinesterase inhibitors. Although it is clear that the drugs increase the amount of acetylcholine in the brain, why this improves Alzheimer's symptoms has been unknown. If scientists understood the mechanisms and pathways responsible for improvement, they might be able to tailor better drugs to combat the disease, which costs more than $200 billion annually in the United States alone.