Many candidate drugs fail because they also target proteins essential to life. This discovery from Leuven could form a target for a treatment against Alzheimer’s disease with fewer side effects and that suppresses the very first symptoms of the disease. This research will be published in the leading journal Nature Medicine.
Amantha Thathiah (VIB/KU Leuven)
Alzheimer’s Disease is the most common form of dementia in the West. The damage to memory and mental function causes one of the most terrifying clinical pictures. The current drugs for Alzheimer patients support memory for a short time, but they do not stop the death of brain cells. Recent insights have shown that Alzheimer’s disease causes biochemical changes in the brain many years before the symptoms of dementia are present. It is very important to develop drugs that can be taken at this early stage in order to prevent the disease.
The ɣ-secretase complex
Many candidate drugs have an effect on the ɣ-secretase complex. This complex cuts proteins at specific sites and plays an important role in the development of amyloid plaques, a pathological hallmark in of the brains of Alzheimer patients. Aberrant and excessive cleavage of the amyloid precursor protein by the -secretase complex results in the accumulation and deposition of the -amyloid protein in amyloid plaques.
However, the ɣ-secretase complex is also involved in cleavage of a series of other proteins essential to life. As a result, many candidate drugs that act on the ɣ-secretase complex produce toxic side effects.
GPCRs and β-arrestin
GPCRs are a family of proteins that serve as the targets of the majority of all currently marketed drugs. The Nobel Prize in Chemistry for 2012 was awarded to Dr. Robert Lefkowitz and Dr. Brian Kobilka for their groundbreaking work in this field and the many medical applications of this knowledge. It is known that GPCRs also play a role in the development of Alzheimer’s disease, but it is not yet clear how GPCRs regulate the ɣ-secretase complex.
β-arrestins are a family of proteins that classically block or limit GPCR activation; however, it has been recently appreciated that -arrestins also have additional functions. Therefore, Amantha Thathiah set up a study to examine the involvement of β-arrestins in the development of Alzheimer’s disease.
The scientists succeeded for the first time in demonstrating that β-arrestin 2 plays a role in regulation of the ɣ-secretase complex function and in the development of Alzheimer’s disease in an Alzheimer’s disease mouse model. More specifically, β-arrestin 2 interacts with two GPCRs that are known to play a role in the development of Alzheimer’s disease. Moreover, expression of -arrestin 2 is also elevated in individuals with Alzheimer’s disease.
Impact of the research
This research opens a new pathway for the treatment of Alzheimer’s disease. -arrestin 2 inhibition could be beneficial in prevention of the adverse side effects currently associated with γ-secretase inhibition. Therefore, this study provides a previously unexplored avenue for the development of a treatment that can act at a very early stage of Alzheimer’s disease.
Relevant scientific publication
This research will be published in the leading journal Nature Medicine, Thathiah et al., β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer’s disease
This research was performed in the research group of Bart De Strooper in the VIB Research Centre for Developmental Mechanisms of Diseases, KU Leuven
This research was funded by VIB, MNIRG from the Alzheimer’s Association, the Fund for Scientific Research Flanders, K.U. Leuven, a Methusalem grant from the K.U. Leuven and the Flemish government, the foundation for Alzheimer Research (SAO/FRMA).