Drosophila needs APP-like protein in its full-length form to maintain working memory and prevent age-related memory impairment
14 March 2018
Humans are not the only species to exhibit signs of memory impairment as they get older. Animals also suffer from age-related memory loss, and the fruit fly Drosophila melanogaster is no exception. In their middle age, i.e., when they are 30 to 40 days old, these insects display signs of inadequacy with regard to their mid- to long-term olfactory memory. Scientists at Johannes Gutenberg University Mainz (JGU) have discovered now that the insects' orientation memory also suffers. They established that the functioning of a protein that plays an important role in Alzheimer's disease is also at center stage in this context in the case of Drosophila.
Fruit flies can remember exactly where they originally intended to go if they are distracted temporarily during their journey. Their visual memory stores the appropriate direction for around four seconds. The team of neurobiologists led by Professor Roland Strauss at Mainz University subjected young and old fruit flies to a test. They showed the insects an orientation point that was within a circular experimental arrangement. The first orientation point would then be made to vanish and a second orientation point would be displayed in its place towards which the flies would realign their direction of flight. When the second orientation point also disappeared, about 80 per cent of young flies were able to remember the position of their original destination and fly towards it. Older flies, on the other hand, had difficulties: Insects aged four weeks had a significantly poorer memory than younger insects and those aged six weeks seemed to forget entirely.
Cleavage of APP-like protein increases with age and is associated with memory loss
"Our results clearly show that visual working memory deteriorates with age," said Franziska Rieche, lead author the study recently published in Current Biology. "We also discovered that this decline in memory can be stopped." A protein known in humans as amyloid precursor protein (APP) plays a pivotal role in this process. A protein similar to APP is present in Drosophila's nerve cells. As demonstrated by Franziska Rieche, a decline in working memory as age increases goes hand in hand with increased cleavage of the full-length protein into fragments. If this cleavage process was inhibited in older fruit flies, they maintained a perfect memory. Conversely, memory decline happened at a faster rate when this process was accelerated. The effect is attributable to three enzymes, so-called secretases, which break down the protein. The greater the concentration of enzymes, the greater the number of fragments.
"The way in which the enzymes cleave the full-length protein into fragments in Drosophila is very similar to what happens in the case of human APP," explained Rieche. In humans, the ß-amyloid that is cleaved from APP by two enzymes is considered responsible for the plaque accumulation characteristic of Alzheimer's disease.
A well-functioning short-term memory in fruit flies therefore depends on the presence of the APP-like protein in its full length. Hence, in experiments using a protein variant that cannot be cleaved, no such memory deterioration was observed. Rieche also discovered a mechanism of action whereby the APP-like protein suppresses the fasciclin II receptor in the cell membrane while, vice versa, increased cleavage of the APP-like protein reduces the fasciclin II receptor suppression and thereby triggers the decline in memory.
Memory regulation system for at least 580 million years
"It is quite astonishing that a memory regulation system like this has survived for more than 580 million years," pointed out Professor Roland Strauss, head of the working group at JGU, referring to the striking similarities between the basic mechanism in Drosophila and in humans, including the proteins and secretases involved. The two phylogenetic trees separated around 580 million years ago. Strauss also noted that the team's findings with regard to physiological functioning apply specifically to the visual working memory of fruit flies that is located in 40 neural rings, 20 in each cerebral hemisphere.
"It will be interesting to find out what type of processing is required for other types of memory," he concluded. "We are currently working on long-term memory. The corresponding cells do not contain fasciclin, meaning that another mechanism of action must be involved." However, the appropriate regulation of APP-like protein appears to be of relevance to all types of memory, even if different forms of processing are required.