Alzheimer’s disease (AD) affects millions of people worldwide. Currently, no cure exists. The project aims to improve understanding of the structural origins of the disease by studying the structural changes occurring in the key proteins Aβ and presenilin involved in the disease.
WHO estimates that more than 30 million people worldwide suffer from AD, a devastating neuro-degenerative disease that involves loss of memory, mood swings, changes in behavior, and loss of bodily functions. Despite the impact of the disease and extensive research efforts, no efficient cure has yet been developed, and it is expected that more molecular mechanism-based strategies are necessary.
Brains of Alzheimer’s patients contain large amounts of aggregated misfolded protein deposits known as “senile plaques”. These are mainly composed of metal ions and Aβ peptides organized as β-sheet structured fibrils.
AD mainly occurs sporadically, but a small portion (3-5 %) of cases are connected to genetic mutations. These familial AD (FAD) cases provide a strong basis for studying the structural causes of the disease. The FAD cases are generally characterized by early onset and display a purer form of the structural deviations than the sporadic cases where a mix of several age-related effects is often seen.
FAD is typically associated with genetic mutations in the genes coding for amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). These mutations are all related to Aβ.
In the project, fundamental structural origins of Aβ and PSEN1 that drive disease severity were identified. Using different force field methods and molecular dynamics simulations the project defined the most important structural types of Aβ and correlated these against experimental data to define the structures that explain experimental data relevant to disease. The project shows that simple, specific conformational features such as coil, helix and solvent availability of genetic Aβ variants correlate with their toxicity, and these hotspots are thus of interest as new targets of more specific, tailored antibodies.
Using EPR, CD, NMR, and fluorescence spectroscopy techniques, the normal and two mutant Aβ forms were studied that are protective and pathogenic, respectively, to enable a model system of the disease. Distinct structural and aggregation behavior was observed that correlates with disease manifestation. The Cu2+ binding site of Aβ was studied and shown to enforce the differences, consistent with a known role of copper-Aβ interactions as probably central to the disease. The project also studied PSEN1, the catalytic subunit of γ-secretase which is responsible for releasing Aβ peptides into the extracellular space of neurons. Using meta-analysis, the project found significant correlations between clinical patient data and specific changes in fundamental structural and chemical properties such as hydrophobicity and stability of the PSEN1 mutants. Also, major structural changes were discovered in the PSEN1 subunit which controls access to the enzyme that produces Aβ and aids in positioning and cleavage of substrates, and this led to a new model of how long vs. short Aβ peptides are formed, and the classification of three conformation states of the protein that directly controls the ratio of their production (the longer forms are considered to be more pathogenic).
Hopefully, the research findings presented will be helpful in designing new strategies for treating AD.
llustartion:
Graphic representation of healthy and Alzheimer’s disease brain showing amyloid beta plaques and tau protein.