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A defining feature of Alzheimer’s disease is the abnormal, sustained accumulation of protein aggregates such as tau inside brain cells, which disrupts the cells’ normal functions. As time passes, brain cells stop working and die, leading to a gradual decline of memory and thinking skills and other symptoms of this devastating condition.

One goal of researchers is to find ways to reduce or stop the accumulation of tau and other related proteins to slow down or prevent disease progression. At 91������Ƶ and the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital a team of researchers has just taken a step in that direction. They have discovered that reducing the levels of a protein called Slingshot-1 has the unanticipated effect of improving Alzheimer’s features in animal models and human cells in the lab. The study appeared in the journal Autophagy.

Cytoskeleton genes and a fruit fly model of Alzheimer’s led to an unanticipated discovery

“We focused our study on genes that participate in the remodeling of the cytoskeleton, a vast, dynamic network of protein fibers that living cells use both as a scaffolding that provides internal structural support and a highway system that transports proteins and cellular components inside the cell,” said corresponding author Dr. Juan Botas, professor of molecular and human genetics and of molecular and cellular biology at Baylor. Botas also is the director of the High Throughput Behavioral Screening Core at the Duncan NRI. “Previous studies by other groups have shown that abnormalities in the cytoskeleton are associated with neurodegeneration, the gradual, progressive breakdown and loss of brain cell function as it is seen in Alzheimer’s disease.”

Botas and his colleagues worked with a laboratory fruit fly model of Alzheimer’s disease that recapitulates many features of the human condition. For instance, model flies progressively lose their ability to move as they age, which the researchers can measure.

In the fruit fly model, the team systematically studied many genes that contribute to cytoskeletal remodeling. They changed the normal expression of each gene and determined the effect of the change on the progression of the disease in the flies.

“Of all the genes we studied, Slingshot-1 caught our attention because decreasing its expression, which led to reduced levels of the protein, improved the movement impairments typically observed in aged fly models of Alzheimer’s,” Botas said. “We then looked into the flies’ mini brains.”

The brains of aged Alzheimer’s fruit flies have accumulated tau protein aggregates, as in human brains with the condition. “Reducing Slingshot-1 levels not only improved the flies’ ability to move but also reduced the accumulation of tau in the flies’ brains,” Botas said. “But how was tau accumulation reduced?”

Revving up the cell’s waste disposal and recycling center

To answer this question the team switched from flies to human cells and found that having less Slingshot-1 protein boosted a cell’s waste disposal and recycling mechanism called autophagy. Cells dispose of or recycle materials, like damaged parts and old or defective proteins, by enclosing them in bubble-like structures, or vesicles, called autophagosomes. These structures fuse with lysosomes, vesicles that contain enzymes that break down the content of the autophagosome.

“We found that reducing the activity of Slingshot-1 increased the number of autophagosomes neural cells formed, which in turn increased the cells’ ability to eliminate tau aggregates and consequently improved neurological function, which we observed as improved movement in the fly model system,” Botas said. 

Can autophagosomes help reduce other protein aggregates?

Importantly, this mechanism led the researchers to predict that, in addition to tau, other proteins that accumulate in the brain causing neurodegenerative conditions also could be degraded by enhanced autophagosome activity, potentially improving the condition. 

“We tested that possibility in the case of alpha-synuclein, a protein whose accumulation is the hallmark of Parkinson's disease and also accumulates in many cases of Alzheimer's disease,” Botas said. “We were excited to find that reducing Slingshot-1 activity also reduced alpha-synuclein accumulation in animal models. It turned out that by improving the cells’ natural capacity for autophagy we could reduce the effects of tau or other protein accumulation in the brain. Furthermore, there is a possibility of translating these findings into therapy.”

The protein Slingshot-1 is a phosphatase, a type of enzyme for which it has been possible to develop drugs to inhibit its activity. “Scientists have developed drugs that block the activity of other phosphatases, we anticipate that a drug can be developed to cross the blood-brain barrier and inhibit Slingshot-1 activity,” Botas said.

First author Morgan C. Stephens, Richard I. Han, Alma M. Perez, Hilary Chester, Maria de Haro, Arsh Ali, Amy Hammett, Ruhee Dere and Ismael Al-Ramahi, all at 91������Ƶ and/or the Duncan NRI, also contributed to this work.

This work was supported by NIH grants U01AG072439, F31NS129062 and R01AG074009.