Sleep and a drug for epilepsy reduce the excitability of nerve cells. The results of a study carried out on fruit flies by researchers at the University of Fribourg suggest that perhaps this approach could serve as a remedy for memory deficits that arise during the early stages of Alzheimer’s disease.

Alzheimer’s disease is the most common cause of dementia in older people. According to figures from the Gesellschaft Alzheimer Schweiz, there are currently almost 150,000 people living with dementia in Switzerland. Moreover, as a result of demographic developments, the number of cases is likely to more than double by 2050. Alzheimer’s is associated with a progressive decline in cognitive function and a gradual loss of memory; many patients also develop sleep disorders.

Twisted protein fragments
“The causes and disease mechanisms of Alzheimer’s are not yet well understood”, says Simon Sprecher, professor in the Department of Biology at the University of Fribourg. However, twisted protein fragments in the intercellular spaces of brain cells seem to play an important role. When fruit flies or mice are genetically engineered to produce more of these twisted, clump-forming protein fragments, called amyloid beta, they develop symptoms similar to those of Alzheimer’s disease.

Well learned, but quickly forgotten
“We knew that fruit flies increasingly show learning problems when they form amyloid beta in all their nerve cells”, adds Sprecher. “But when we limited production of protein fragments to the memory centres in the brains of the fruit flies, we were amazed to find that they learn just as well as the control flies.” Learning means that fruit flies associate one specific scent with a punishment (e.g. electricity surges) and another with a reward (e.g. sugar).

The genetically modified fruit flies avoided the smell associated with punishment just as often as the genetically unmodified flies. As little as two hours later, however, they had a poorer memory of what they had learned. In other words, the fruit flies with amyloid beta forgot faster.

Sleep can reduce memory decay
In further experiments, the researchers treated the fruit flies with a drug for epilepsy or with a sleeping pill. This treatment remedied the memory deficits in the genetically modified fruit flies. “Sleep plays an important role in preventing memory decay caused by amyloid beta”, wrote Sprecher’s team in the journal “PLOS Biology”.

Both the drug for epilepsy and sleep reduced the excitability of nerve cells. It is precisely these nerve cells that are excessively excitable in patients during the preliminary stages of Alzheimer’s disease. Therefore, Sprecher suspects that forgetfulness is related to the activity of the brain cells. In fact, experiments with genetically modified fruit flies with reduced brain cell activity showed that their memory performance could be improved. “Forgetting is an active and strictly regulated biological process”, the researchers state in their article.

Model of early Alzheimer’s disease
Sprecher’s team attributes the fact that genetically modified fruit flies only have memory problems and not yet any learning difficulties to the fact that the spread of amyloid beta lumps was limited to the olfactory centres. The researchers now have a model of early Alzheimer’s disease at hand. “A better understanding of these early stages is of particular interest”, says Sprecher. “Because hopefully this will provide insights into how the course of the disease can be slowed down or, ideally, even stopped.”

Reference:
Kaldun JC, Lone SR, Humbert Camps AM, Fritsch C, Widmer YF, Stein JV, and Sprecher SG. (2021) Dopamine, sleep, and neuronal excitability modulate amyloid-β–mediated forgetting in Drosophila. PLoS Biol 19(10): e3001412. DOI: https://doi.org/10.1371/journal.pbio.3001412