P4‐448: Frailty and other predictors of the quality of life for people with Alzheimer's disease

Background: Alzheimer’s disease (AD) is the most common of the conformational neurodegenerative disorders. Current treatments for AD are largely symptomatic and minimally effective. Major problems with previous immunotherapeutical approaches include: the potential of toxicity from autoimmune encephalitis, tau related pathology not being addressed, and the need to effectively clear congophilic angiopathy (CAA). In our current study we developed a novel immunomodulatory therapeutic approach that would use polymerized British amyloidosis (pABri) related peptides with no homology to any human protein; and polymerized -non-fibrillizedAs1-42 peptide (pAs42), to help overcome these limitations of vaccination. Previously, we have shown that pABri can induce behavioral benefits in APP/PS1 Tg mice associated with reductions in As oligomers. Currently, we tested this approach in mice with both plaques and tangle pathology (3xTg mice) and mice with extensive CAA (TgSwDI). Methods:We produced pABri and pAs42 which by electron microscopy form oligomer-like structures, and by circular dichroism analysis are mainly s-sheet. These were used as immunogens in 3xTg mice as well as in TgSwDI mice, using alum as an adjuvant At the age of 17-18 months the mice were subject to locomotor and cognitive behavioral testing, followed by histological and biochemical analysis. Results: Locomotor testing showed no significant differences between any group in both models. On radial arm maze testing the 3xTg showed the pABri vaccinated and wild-type controls to behave similarly and to differ significantly from 3xTg controls (p <0.01). The analysis of TgSwDI showed the pABri and pAs42 vaccinated and wild-type controls differing significantly from the TgSwDI controls (p <0.001). The pABri inoculated animals made low titers of IgM and IgG recognizing the original antigen and oligomerized As42. Animals inoculated with pAs42 had high titers of anti-As peptides plain or oligomerized. All animals remained healthy and without noticeable autoimmune complications for the length of the experiment. Histological and biochemical analysis is on-going in these animals. Conclusions: A novel active immunomodulation approach that targets the shared abnormal conformation found in aggregated/oligomer As and PHF is associated with a mild poly-reactive immune response mainly against oligomeric forms and significant cognitive benefits in both 3xTg and SwDI Tg model mice.