Amyloid protein fibrils are associated with a group of devastating human diseases. The precise etiologic agents for these medical conditions remain undefined, but in several cases appear to be protein fibrils or pre-fibrillar oligomers. Currently there is no approved therapeutic agent that regulates the formation of amyloid fibrils and reverses the symptoms. Our working hypothesis is that interfering with amyloid fibrillation and oligomerization is of clinical benefit to patients suffering from Alzheimer's and other amyloid diseases. Amyloid proteins lack common sequence motifs;nevertheless, they display similar biophysical characteristics and a common 'cross-B spine'structure. The first fully objective atomic model of the common B-spine structure of a fibril-forming peptide was determined in our lab, and additional structures are already available. Based on these atomic structures, we are able to design inhibitors. Our recently designed peptide inhibitors of tau fibrils, based on the structure of the amyloid spines of the tau protein determined in our lab, interfere with fibrillation of tau. We plan to improve the bioavailability and potency of these inhibitors and to design similar peptide inhibitors against Amyloid-beta (AB) fibrils. In recent years several compounds were shown by others to inhibit fibrillation, although the molecular mechanism of this interference is not yet clear. We will determine crystal structures of the fibrils bound to various inhibitors that will advance our understanding of the mechanism of inhibition of fibrils and small oligomers by small molecule inhibitors. The structure determination will be coupled to a computational approach to detect non-toxic, specific and potent inhibitors that will cross the blood-brain-barrier and will bind strongly to fibrils and oligomers. Another important application of this study is to find compounds that could be useful as markers for fibrils in biochemical assays as well as in the diagnosis of fibrils in-vivo. Our project is consistent with the aims of """"""""The Therapeutic Imperative"""""""", and our proposal involves dose collaboration with members of the ADRC community.
New treatment for Alzheimer's disease are urgently needed. Alzheimers appears to result from proteins that change their structure and kill nerve cells. This project will develop treatments that keep the proteins from changing structures. These agents may be new treatments for Alzheimer's disease.
|Chang, Timothy S; Teng, Edmond; Elashoff, David et al. (2016) Optimizing Effect Sizes With Imaging Enrichment and Outcome Choices for Mild Alzheimer Disease Clinical Trials. Alzheimer Dis Assoc Disord :|
|Green, Colin; Zhang, Shenqiu (2016) Predicting the progression of Alzheimer's disease dementia: AÂ multidomain health policy model. Alzheimers Dement 12:776-85|
|Hohman, Timothy J; Cooke-Bailey, Jessica N; Reitz, Christiane et al. (2016) Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk. Alzheimers Dement 12:233-43|
|Hohman, Timothy J; Bush, William S; Jiang, Lan et al. (2016) Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium. Neurobiol Aging 38:141-50|
|Ramirez, Leslie M; Goukasian, Naira; Porat, Shai et al. (2016) Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy. Neurobiol Aging 39:82-9|
|Filshtein, Teresa; Beckett, Laurel A; Godwin, Haley et al. (2016) Incident Antipsychotic Use in a Diverse Population with Dementia. J Am Geriatr Soc 64:e44-6|
|Clark, David Glenn; McLaughlin, Paula M; Woo, Ellen et al. (2016) Novel verbal fluency scores and structural brain imaging for prediction of cognitive outcome in mild cognitive impairment. Alzheimers Dement (Amst) 2:113-22|
|Lin, Amy; Brook, Jenny; Grill, Joshua D et al. (2016) Participant-Informant Relationships Affect Quality of Life Ratings in Incipient and Clinical Alzheimer Disease. Am J Geriatr Psychiatry :|
|Porat, Shai; Goukasian, Naira; Hwang, Kristy S et al. (2016) Dance Experience and Associations with Cortical Gray Matter Thickness in the Aging Population. Dement Geriatr Cogn Dis Extra 6:508-517|
|Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy et al. (2016) The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable. Neurobiol Aging 41:115-21|
Showing the most recent 10 out of 651 publications