B-amyloid peptide (Ab), the primary protein component of senile plaques in Alzheimer's disease (AD), plays an important role in neurotoxicity and is a marker for disease progression. Increasing evidence, both in our lab and others, indicates that Ab binds with relatively high affinity to clustered sialic acid residues on cell surfaces. We hypothesize that membrane mimicking clustered sialic acid residues conjugated to dendritic polymers can be designed with sufficiently high Ab affinity that they will be useful in both Ab detection and Ab toxicity inhibition. More specifically, we believe that we can exploit the relatively high affinity binding of sialic acid clusters to aggregated/fibril Ab for 1) the detection of Ab deposits in vivo associated with amyloid plaques present in Alzheimer's disease; 2) the detection of soluble amyloid oligomers present in biological tissues such as cerebral spinal fluid or post mortem tissue samples; and 3) for capturing soluble (but toxic) Ab oligomers in vivo, therefore making them unavailable for binding (and killing) cells. In order to test this hypothesis, we will synthesize a number of different sialic acid modified dendritic polymers, measure their affinity for soluble aggregated Ab, insoluble, fibril Ab, and soluble, unaggregated Ab, relative to other extracellular proteins of the CNS, assess the ability of these sialic acid dendrimers to prevent Ab toxicity in vitro, and use the dendrimers in the development of fluorescence and surface enhanced Raman detection method for Ab in vitro. This work is the first step in developing diagnostic and therapeutic agents for use in vivo for the detection and prevention of Alzheimer's disease.
| Cowan, Christopher B; Patel, Dhara A; Good, Theresa A (2009) Exploring the mechanism of beta-amyloid toxicity attenuation by multivalent sialic acid polymers through the use of mathematical models. J Theor Biol 258:189-97 |
| Cowan, Christopher B; Cote, Gerard L; Good, Theresa A (2008) Development of photocrosslinked sialic acid containing polymers for use in Abeta toxicity attenuation. Biomaterials 29:3408-14 |
| Chou, I-Hsien; Benford, Melodie; Beier, Hope T et al. (2008) Nanofluidic biosensing for beta-amyloid detection using surface enhanced Raman spectroscopy. Nano Lett 8:1729-35 |
| Patel, Dhara A; Henry, James E; Good, Theresa A (2007) Attenuation of beta-amyloid-induced toxicity by sialic-acid-conjugated dendrimers: role of sialic acid attachment. Brain Res 1161:95-105 |
| Patel, Dhara; Henry, James; Good, Theresa (2006) Attenuation of beta-amyloid induced toxicity by sialic acid-conjugated dendrimeric polymers. Biochim Biophys Acta 1760:1802-9 |
