Ben Seyer

A very prominent feature of Alzheimer’s disease is the loss of dendritic spines. These spines form the connections between our neurons, or brain cells. These connections are critically important to the way our brain processes and retains information. As we remember events, more of these connections are made between our neurons which in effect physically stores the memory. In Alzheimer’s these connections are destroyed which causes sufferers to forget previous memories while also making it harder for now ones to form.

The lab, which Ben is apart of, has developed a drug series that targets a protein in the brain known as IRAP (Insulin-Regulated AminoPeptidase). By targeting this protein we have been able to improve memory in mice which develop Alzheimer’s disease. Further he has also shown that this drug can increase the growth of dendritic spines between neurons. Research is now directed at examining how this effect takes place  

Another key feature in Alzheimer’s is an ability of the brain to properly utilise it’s primary energy source, glucose (a simple sugar). This means that many of the protective mechanisms that exist within the brain may not function effectively thus leading to the damage associated with the disease. The drug is able to increase the uptake of glucose by brain cells and this could explain the beneficial effects it has on memory and dendritic spine number and work is now being performed to examine this possibility.

The initial stages of the project have focused on establishing a number of novel techniques in the laboratory to assess the different aspects of IRAP inhibitors treatment on memory enhancement, brain plasticity and within Alzheimer’s.

Previous evidence has shown that treatment with HFI-419 (a synthetic IRAP inhibitor developed by our lab) can enhance spatial working and recognition memory. Work is now being directed at examining specifically what forms of memory are enhanced (acquisition, encoding, retrieval) as well how these benefits are conferred. In order to achieve this the behavioural testing paradigm has been re-established within the lab.

HFI-419 treatment can also increase dendritic spine number (a marker of increased cognitive status) in primary hippocampal cell culture. This protocol has now been established and will allow the screening new inhibitor compounds with much greater efficiency while also permitting detailed examination of the mechanisms by which spine density is increased.

Within the APD9 mouse model of Alzheimer’s, HFI-419 treatment is able to restore memory and learning. The dendritic spine density within the hippocampus (a key area of the brain involved in learning) of these animals is being assessed with the prediction that inhibitor treatment will rescue reductions in spine density that are present within the APD9’s compared to wild-type mice.

Cerebral hypometabolism is another key symptom of Alzheimer’s and previous has shown HFI-419 can enhance glucose within the brain. Detailed examination in both in vivo and in cell culture will examine how this effect is achieved and whether it responsible for the memory and dendritic spine enhancements seen in response to inhibitor treatment.

Ben is currently finalising and completing his PhD Thesis which is due for submission in 2015.