Scientists from VIB and KU Leuven have discovered a new target molecule for the development of a treatment against Alzheimer's disease. The discovery could form a target for a treatment against Alzheimer's disease that suppresses the very first symptoms of the disease and does so with fewer side effects. The research is being published in the leading journal Nature Medicine.
Alzheimer’s disease is the most common form of dementia in the western world. Current medications 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 the brains of Alzheimer patients. Aberrant and excessive cleavage of the amyloid precursor protein by the ɣ-secretase complex results in the accumulation and deposition of the β-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.
Fewer side effects
GPCRs are a family of proteins that serve as the targets of the majority of all currently marketed drugs against Alzheimer's disease. 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.
Another family of protiens – β-arrestins – play an important role in GPCR activation. While β-arrestins have classically been known to limit or block GPCR activation, it has been recently shown that b-arrestins also have additional functions. To begin uncovering them, Amantha Thathiah set up a study under the supervision of Bart De Strooper 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 the regulation of the ɣ-secretase complex function and thus in the development of Alzheimer’s disease. More specifically, β-arrestin 2 interacts with two GPCRs that are known to play a role in the development of Alzheimer’s disease.
This research opens a new pathway for the treatment of Alzheimer’s disease. β-arrestin 2 inhibition could be beneficial in prevention of the adverse side effects currently associated with γ-secretase inhibition. The study points the way to a previously unexplored avenue: a therapy for very-early-stage Alzheimer’s disease with fewer side effects than other candidate medications.
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