Alzheimer's disease / Neuropharmacology
Alzheimer’s disease is the most common cause of age-related dementia, and a major societal problem due to the lack of efficacious therapeutics.
The disease is likely caused by the accumulation of protein aggregates, amyloid-β and tau, leading to proteinaceous deposits in brain tissue.
It is vital to understand disease mechanisms and key points of pathogenesis that could serve as drug targets, but also to find biomarkers that could be used for diagnosis and effect evaluation of drug candidates.
The innate immune system in Alzheimer’s disease
In recent years, a number of genes predisposing to Alzheimer’s disease have been identified. Several of them are linked to innate immunity or lipid metabolism.
One of them, TREM2, is a strong genetic risk factor for Alzheimer’s disease and some coding variants of TREM2 result in other neurodegenerative disorders.
The TREM2-reseptor is expressed in microglia, the immune response cells of the brain, and functionally coupled to innate immunity and clearance of amyloid-b aggregates by phagocytosis.
The study aims to
- Explore signaling mechanisms coupled to activation of the TREM2 receptor and essential to microglial function in vitro, including effects of Alzheimer’s disease risk factor Apolipoprotein E which has been shown by us to be a TREM2-ligand
- Analyze TREM2 and TREM2-fragments in cerebrospinal fluid as to better understand their physiological functions in human, and evaluate their potential as biomarkers
- Investigate TREM2-expression in transgenic mice models and post mortem brain of Alzheimer’s disease patients
Trem2-based drug development for the treatment of Alzheimer’s disease
There is no medical treatment available that slows disease progression. With an aging population and huge costs for dementia care, there is a great need for such a drug.
The disorder is characterized of proteinaceous deposits of amyloid-β in brain. Trem2 serve to facilitate the clearance of amyloid-b aggregates and it also affects neuroinflammation.
The study aims to
- Establish a screening assay to identify drug candidates binding to and affecting TREM2-reseptor signal transduction thereby enhancing TREM2-based microglial function
- Generate an animal model of Alzheimer’s disease expressing human TREM2 protein enabling efficacy evaluation of drug candidates from screening
- Examine if drug candidates identified by screening bind to the TREM2-receptor in human post mortem brain tissue
- Evaluate effects and pharmacokinetic properties of drug candidates in an animal model of Alzheimer’s disease