A team of researchers at the University of Texas Southwestern Medical Center may have found a way to prevent Alzheimer’s disease from clogging brain tissue. Their novel approach could be turned into a drug or vaccine that would prevent the debilitating disease in 50 to 80% of at-risk adults.
Alzheimer’s is the leading cause of dementia. The neurodegenerative disease affects cognitive and thinking abilities, making day-to-day life incredibly challenging in its most advanced stages.
After a certain age, the human brain starts to shrink considerably but surprisingly, not too many neurons die in the process. In the Alzheimer’s diseased brain, however, many neurons stop functioning, lose connections with other neurons, and eventually die.
In the early stage, the damage is confined to the entorhinal cortex and hippocampus, two areas associated with memory, navigation, and perception of time. This sort of degeneration leads to memory loss and disorientation associated with the condition — though it has to be noted that Alzheimer’s starts damaging brain cells well even before the first symptoms kick in.
Later on, the disease starts to hit the cerebral cortex responsible for language, reasoning, and social behavior, from where it eventually spreads to other brain areas.
Research has shown that individuals with Alzheimer’s disease accumulate beta-amyloid proteins which clump together to form plaques between neurons and disrupt cell function. Another physical characteristic of the Alzheimer’s diseased brain is the buildup of tau proteins. which tangle inside neurons blocking the cells’ transport system.
Currently, there is no available cure for Alzheimer’s disease. Most research efforts are focused on findings ways to halt the progress of the disease and reduce its symptoms. However, molecular biologist Joachim Herz and colleagues at UT Southwestern have embarked on a different route: instead of looking for ways to stop the spread of amyloid and tau accumulation when the process has already set in, the researchers are looking to prevent the buildup from happening in the first place. In other words, they want to prevent the disease rather than treat it.
There are three major forms of Apolipoprotein E (ApoE) proteins that play a vital role in the brain tissue repair by carrying lipids and cholesterol around the brain. However, individuals who carry ApoE4 are up to 10 times more likely to get Alzheimer’s than those with the ApoE2 and ApoE3 forms.
Herz and colleagues claim that ApoE4 causes “traffic jams” inside neuron cells, thereby leading to inefficient recycling of intracellular endosomal transport vesicles. Their research on mice found that lowering the pH of these endosomes (making them more acidic) cleared the traffic jams. Specifically, the ApoE4-induced blockages were reversed by inhibiting the NHE6 protein, which is responsible for making endosomal vesicles less acidic.
“Our approach in this study was to stop the overall degeneration process earlier; that is, before the formation of these aggregates [i.e. amyloid and tau protein],” Dr. Herz said in a statement.
The findings provide a new therapeutic pathway that could prevent Alzheimer’s in 50% to 80% of at-risk adults. A vaccine or drug that selectively blocks NHE6 could be administered before age 40, providing a lifetime of Alzheimer’s protection. Developing such tailor-made molecules is the next step for the UT Southwestern researchers.
“The beauty of NHE inhibitors is that these are small molecules that can be produced inexpensively and thus made widely available, in contrast to the more elaborate antibody-based therapies that are currently being evaluated in clinical trials. A simple pill could someday neutralize the risk of late-onset Alzheimer’s disease just as readily available statins are able to reduce the risk of cardiovascular disease,” Dr. Herz said.
The findings were reported in the journal eLife.
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