Alzheimer’s disease is characterized by progressive accumulation of protein aggregates of amyloid beta and tau in selected brain regions. This accumulation of protein aggregates results from an imbalance between protein synthesis, aggregation and clearance.
To understand, and control the mechanisms involved in this imbalance, we need to investigate all interconnected steps in this process. There are evidence that the autophagy-lysosomal compartment apart from clearance of amyloid beta also is part of both amyloid beta generation and aggregation.
Lysosomes in focus for development of diagnostic tools and new treatment strategies
Our research work focuses on autophagy-lysosomal function in relation to Alzheimer’s disease pathology. We have discovered that aberrant accumulation of amyloid beta in lysosomes occurs in an autophagy dependent fashion upon proteasomal inactivation or oxidative stress conditions. The accumulation of amyloid beta in lysosomes leads to cell death.
In a series of investigations we have demonstrated lysosomal membrane permeabilization with release of lysosomal proteases to the cytosol to be critical for the onset of apoptotic cell death. Therefore, neuronal death in Alzheimer’s disease might be due to a combination of lysosomal events where lysosomal dysfunction leads to an upregulation of autophagy, which results in both an increased transport of Aβ to the lysosome and generation of Aβ with ensuing neuronal death.
We have also discovered that cholesterol can modify the stability of the lysosomal membrane. Interestingly, we found the lysosomal cholesterol transporting protein Niemann-Pick type I to be overexpressed in brains from Alzheimer patients. Ongoing studies in our group centers on modifying lysosomal stability and function in an Alzheimer context.
We aim at being part of exploiting new therapeutic strategies and develop new diagnostic tools for Alzheimer’s disease. This research is predominantly at a molecular and cellular level and is complemented by modeling of Alzheimer’s disease in Drosophila melanogaster, CSF and human brain tissue.