The protein low density lipoprotein receptor related protein 1 (LRP1) plays
multiple roles in the biology of amyloid β peptide (Aβ) and Alzheimer’s disease. LRP1 is
very important for clearance of Aβ both in the brain and by facilitating Aβ export over the
blood brain barrier. In spite of the apparent importance of LRP1, little is known about the
molecular mechanisms of the interaction with Aβ. Herein, I report the affinity between the
double domains of the ligand binding complement type repeat (CR) domains from LRP1
and Aβ. Showing that the affinity between CR double domains and Aβ is approximately 4
orders of magnitude lower that that reported for triple CR domains. I furthermore find the
regions in Aβ involved in the binding of CR domains, which may give an explanation for
the lower affinity for double domains than triple domains.
An interesting property of Aβ is its ability to fibrillate, during the process toxic
oligomer species are formed which are possibly the cause of Alzheimer’s Disease. Having
established that LRP1 CR double domains due bind Aβ I also investigated their ability to
inhibit the fibrillation of Aβ42, the more fibrillation prone and toxic variant. The data show
that CR domains have a complex effect on the fibrillation of Aβ42, which is concentration
dependent. At low concentrations CR domains seems to increase the secondary nucleation
and decrease the primary nucleation. At high concentrations the effect is reversed and the
secondary nucleation is decreased while the primary nucleation is increased. The data
furthermore indicates that there is an interaction with Aβ oligomer state and possible also
the fibrils.
Another brain protein is the neuronal protein Activity-regulated cytoskeletonassociated
protein (Arc) which is important for learning and memory. The gene coding for
Arc protein has been domesticated from the same branch of genes that has given rise to
retroviruses. We show that even despite the large evolutional distance between Arc and
retroviruses. Despite large evolutionary distance Arc still self-assemble into higher order
structures that resembles the capsid structures found in retrovirus. By solving the structure
of Arc capsid like domain we show that the ability to form these structures has likely been
suppressed by making the linker between the two domains in Arc capsid like domain
shorter and more rigid. Additionally we investigated the interaction between Arc and Nmethyl-
D-aspartate receptors (NMDAR) showing a direct interaction with the NMDA
subunit GluN2B. This interaction work also lead to a refined binding motif for Arc ligands