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P1‐114: Manganese‐Enhanced Magnetic Resonance Imaging (MEMRI)‐Based Identification of Neuronal Dysfunction Before the Appearance of TAU Pathology in RTG4510 Mice
Author(s) -
Lyons Danielle N.,
Ingram Alexandria,
Meier Shelby E.,
Bell Michelle C.,
Price Brittani,
Cloyd Ryan,
Powell David K.,
Vandsburger Moriel,
Abisambra Joe F.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.862
Subject(s) - neuroscience , hippocampal formation , tau pathology , genetically modified mouse , hippocampus , magnetic resonance imaging , pathological , pathology , atrophy , psychology , cognition , transgene , medicine , chemistry , alzheimer's disease , disease , radiology , biochemistry , gene
Background:Alzheimer’s disease (AD) is considered to be one of the most devastating disorder known for the symptoms as weaken in memory, motor ability, and cognitive ability. AD is characterized by the deposition of amyloid tangles, more specifically, amyloidbeta (Ab), a polypeptide approximately 4 kDa. It is produced from the cleavage of amyloid precursor by secretases into two forms: Ab1-40 and Ab1-42, which Ab1-40 was found to be more abundant in AD.Monomeric formsofAb aggregateswith eachother to formprotofibrils and oligomers which eventually becomes fibrils that causes amyloid tangles in the brain. A humanized antibody Solanezumab was developed by Eli Lilly targeting the neurotoxic Ab peptides for anti-amyloid treatment. Although the outcome of the treatment is still under investigation, the interaction of Solanezumab and Ab became crucial in both the study ofAD. Surface PlasmonResonance analysis was conducted to determine the affinity of such interaction between the antibody and different forms of the Ab protein. Methods: Surface Plasmon Resonance (SPR) binding experiments were performed using a Biacore X100 SPR (GE Healthcare). Guided by the Biotin CAPture Kit (GE Healthcare), The sensor chips were activated using the Biotin CAPture Reagent and immobilized with Biotinylated Ab (Anaspec, CA). Analytes (Solanezumab-scFv) were injected at designated concentrations. To determine the full kinetic profile, protein-small molecules binding spectrograms were evaluated using the Biacore X100 Evaluation Software. Results: Analyses were conducted for both Ab1-40 and Ab1-42. The binding affinity (KD) between Solanezumab and Ab1-40 oligomer were detected to be 0.346 and 0.832 nM at 25 C and 37 C, respectively. On the other hand, the KD between Solanezumab and Ab1-42 oligomers were 0.103 nM and 0.061 nM at 25 C and 37 C, respectively. However, no detectable interactions were observed between the antibody and mature fibril forms of Ab. Conclusions:SPR analyses were performed for the interaction of Solanezumab andAb. The affinity of Ab1-42 oligomer was 3 to 5 times stronger than of Ab1-40 indicating the high efficacy of eliminating the toxic oligomers of Ab1-42. No detectable interactions of Ab fibrils were observed suggesting an unavailability of binding site for the antibody.