Alzheimer's disease (AD) is the most common age-associated neurodegenerative disease, affecting approximately 5 million Americans. Most researchers believe that the deposition of beta-amyloid peptide (Aβ) as extracellular amyloid deposits in the brain, is causally linked to the neuronal dysfunction and death observed in the disease. Aβ is the proteolytic product of a precursor protein called APP. Transgenic mice, engineered to overexpress APP, develop a large number of Aβ deposits. Surprisingly, however, these mice suffer little neuronal death, thus calling into question the “amyloid cascade” hypothesis. Recently, it has been discovered that transgenic mice respond to the overexpression of APP by robustly upregulating synthesis of another protein, transthyretin (TTR). TTR serves as a transport protein in the blood and is the most common protein in cerebrospinal fluid. Remarkably, TTR itself can form amyloid deposits, and is responsible for causing a common age-related disease called senile systemic amyloidosis. We hypothesis that upregulation of TTR in transgenic mice serves a neuroprotective role, but the mechanism of this action is unknown. In this talk we present data showing that TTR interacts directly with Aβ, influencing both its aggregation kinetics and its toxicity. The nature of the interaction is complex, as TTR is a homotetrameric protein and Aβ is present as a mix of monomer, oligomer, and fibril. We produced and characterized recombinant wt TTR as well as mutants that differ in the stability of the tetramer. Our data show that TTR tetramer stability strongly influences the protein's regulation of Aβ aggregation kinetics. Interestingly, those TTR variants that accelerated Aβ aggregation were best at inhibiting Aβ toxicity in cell culture assays. The effect of TTR on Aβ aggregation has been characterized in detail using a variety of biophysical and biochemical tools. Our results delineate the importance of TTR and Aβ monomeric vs. oligomeric status in regulating their interaction. We present some strategies for adjusting TTR tetramer stability through the use of small-molecule drugs, as an indirect method for reducing Aβ toxicity by manipulating this protein-misfolding regulatory network.