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.

Bursts of Brain Activity May Protect Against Alzheimer's Disease

Evidence indicates that the accumulation of amyloid-beta proteins, which form the plaques found in the brains of Alzheimer's patients, is critical for the development of Alzheimer's disease, which impacts 5.4 million Americans. And not just the quantity, but also the quality of amyloid-beta peptides is crucial for Alzheimer's initiation. The disease is triggered by an imbalance in two different amyloid species -- in Alzheimer's patients 

there is a reduction in a relative level of healthy amyloid-beta 40 compared to 42.

Now Dr. Inna Slutsky of Tel Aviv University's Sackler Faculty of Medicine and the Sagol School of Neuroscience, with postdoctoral fellow Dr. Iftach Dolev and PhD student Hilla Fogel, have uncovered two main features of the brain circuits that impact this crucial balance. The researchers have found that patterns of electrical pulses (called "spikes") in the form of high-frequency bursts and the filtering properties of synapses are crucial to the regulation of the amyloid-beta 40/42 ratio. Synapses that transfer information in spike bursts improve the amyloid-beta 40/42 ratio.

This represents a major advance in understanding that brain circuits regulate composition of amyloid-beta proteins, showing that the disease is not just driven by genetic mutations, but by physiological mechanisms as well.