Characterization of rapidly progressive LOAD

 
   Lead Investigator:    Jiri Safar
   Institution      :    Case Western Reserve University
   E-Mail           :    jiri.safar
   Proposal ID      :    1242



   Proposal Description:
   The deposition of aggregated amyloid beta (Ab) and hyperphosphorylated tau proteins is directly associated with cell death and propagation of brain pathology in sporadic as well as familial Alzheimer?s disease (AD). The long-term objective of this research is to define the molecular mechanism responsible for diverse phenotypes and progression rates in AD. To this goal, three principal investigators with complementary expertise will delineate the structural organization, structure/function relationship, and key structural attributes that control distinct pathogenic potential of prion-like strains of Ab and aggregated tau. In the brain tissue from phenotypically distinct cases of sporadic and familial AD, we propose to use for strain-typing of Ab and tau aggregates approaches that were developed and validated in prion research. Apart from massspectroscopy based biophysical studies with brain-isolated strains of Ab and tau aggregates, we will also measure their seeding (replication) potency that relate to the progression rate of disease, and neuronal cell toxicity linked to the pathogenesis of neurodegeneration in AD. Finally, we will obtain high-resolution insight into the structure of in vitro generated high-fidelity replicas of brain-derived Ab and tau filaments corresponding to distinct phenotypes of AD with solid-state NMR spectroscopy. Establishing the relationship between specific structural features of Ab and tau strains should uncover critical aspects of the pathogenesis in distinct forms of AD, key factors responsible for very rapid rate of cognitive decline in significant subset of AD, and test the hypothesis that prion-like strains are responsible for phenotypic diversity and progression rate. This insight is critical for efforts to develop molecular markers that predict progression and phenotype of AD and ultimately for novel therapeutic strategies.