Amyloid-beta not in aggregated form is present in all humans and does not cause disease, but when it starts to clump or aggregate, that is when it becomes toxic. Current treatment methods for Alzheimer’s disease (AD) that are in clinical trials attempt to bind to these disease-causing aggregates. But they are unable to bind to the smallest aggregates. Now researchers at Uppsala University in Sweden report their method in a mouse study degrades the building blocks from which these aggregates form before they have a chance to aggregate.

Their findings, “Enhanced neprilysin-mediated degradation of hippocampal Aβ42 with a somatostatin peptide that enters the brain,” is published in the journal Theranostics.

“Neprilysin is the major Aβ degrading enzyme,” noted the researchers. “…Lower levels of neprilysin have been detected in postmortem brain tissue from AD patients compared to non-AD brains. Importantly, high expression of the naturally occurring neprilysin is associated with a decrease in the accumulation of Aβ in transgenic mouse models of AD. In addition, increased levels of Aβ have been observed in neprilysin knock-out mice, whilst gene therapy approaches with neprilysin lower Aβ pathology and improve cognition in AD mouse models. Neprilysin activity can be increased by the neuropeptide somatostatin (SST).”

Somatostatin is a polypeptide hormone produced chiefly by the hypothalamus. It inhibits the secretion of various other hormones, such as somatotropin, glucagon, insulin, thyrotropin, and gastrin. Studies have reported finding somatostatin to be consistently reduced in the brain and cerebrospinal fluid of AD patients, and activate the body’s own degradation of amyloid-beta. Unfortunately, it has not been possible to use somatostatin as a drug in the past because it has a very short half-life in the blood of only a few minutes, and does not cross the blood-brain barrier into the brain where the aggregates are formed.

The researchers aimed at creating a blood-brain barrier penetrating somatostatin as a potential therapeutic strategy.

“So to be able to use somatostatin as a treatment, we fused it to a brain transport protein which allows the somatostatin to enter the brain,” stated Fadi Rofo, a doctoral student in the department of pharmaceutical biosciences. “This has proved very effective. When we used the transport protein, we also saw that the time that the somatostatin remained in the brain increased to several days, which is fantastic.” The researchers found that SST-scFv8D3, exhibited 120 times longer half-life than SST alone, reached the brain in high amounts when injected intravenously, and significantly increased the brain concentration of neprilysin in mice. A significant decrease in the levels of membrane-bound Aβ42 was detected in the hippocampus and the adjacent cortical area after only three injections.”

“The fact that we have seen that the effect is most evident in the hippocampus in particular is very good. Our hope is that this method will be able to act in a very targeted way and have few side effects, which have been a problem in other studies,” said Greta Hultqvist, assistant professor at the department of pharmaceutical biosciences, who led the research study.

The results reveal a potential therapeutic option that may lead to further studies and may one day lead to clinical trials.

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