Vernon M. Ingram

Visit Vernon Ingram's web page : http://web.mit.edu/fnl/volume/191/ingram.html

We note with sorrow the death of Professor Ingram on August 17, 2006. The Biology Department and the entire biology community is the poorer for his passing.



Overview
Our main concern is to understand the molecular mechanism(s) of certain neurodegenerative diseases, Alzheimer's Disease (AD) and Huntington's Disease (HD), that are due to the formation of misfolded neurotoxic proteins. The structure of these misfolded proteins or peptides is characterized by a great increase in ß-sheet conformation as proteins or peptides aggregate to fibrils. We are currently developing small molecules that reverse this conformational change and thereby eliminate the neurotoxicity and neuronal degeneration. These compounds are the result of a robotic High Throughput Screen. The compounds themselves are being developed for animal trials in AD and HD-transgenic mice, and eventually readied for human trials. At the same time we are characterizing the particular neurotoxic intermediates along the aggregation pathway to understand their unique structure. This will enable us to design even more effective small molecules.



Research Summary
Alzheimer's Disease: Sensitive fluorescent techniques document that the neurotoxic Alzheimer peptide forms ß-sheet-rich fibrils during the spontaneous aggregation, fibrils that are clearly seen in the electron microscope. Surprisingly, our "best" compounds disaggregate and dissolve these fibrils within minutes. Most importantly, the same small molecules also eliminate the neurotoxicity of aggregated peptide, as measured in our sensitive cell-based assay. Our job now is to understand the mechanism for this disaggregation and reversal, using the techniques of protein chemistry that are available here. Through collaborations with organic chemists we can then change the structure of our effective compounds to increase their efficacy. Through the singular molecular mechanism of AD we expect our present and future compounds to be effective for all types of Alzheimer's, both inherited and others.

Huntington's Disease: It turns out that in this fatal disease also, ß-sheet-rich aggregates cause a problem. In HD, however, this aggregation occurs inside neuronal cells. In principle this will make it more difficult to treat HD than AD, because in the latter the vulnerable aggregation occurs outside cells and is more accessible. Nevertheless, the compounds we have that disaggregate AD peptides CAN get into cells. We are developing these for HD animal trials, and eventually human trials.

A very exciting recent development by a graduate student who also works in Chemical Engineering is the selection by yeast display of a very small but highly effective antibody fragment. When expressed in cells, it eliminates HD-specific "misfolded" protein aggregates.



Selected Publications
Blanchard B.J., Chen A., Kelly C., Stafford K., Stockwell B. & Ingram V.M. Novel Compounds eliminate the Neurotoxicity of the Alzheimer Aß Peptide. Abstr. Massachusetts Alzheimer’s Disease Research Center, Annual meeting (2004).

Ingram V.M., Blanchard B.J., Chen A., Kelly C., Stafford K. & Stockwell B. Blocking the Initial Molecular Mechanism of Alzheimer’s Disease. Abstr. International Congress on Alzheimer’s Disease, Philadelphia (2004).

Ingram, V.M. Sickle Cell Anemia hemoglobin: The Molecular Biology of the First ‘Molecular Disease’ Genetics 167:1-7 (2004).

Ingram V.M. The Role of Alzheimer Aß Peptides in Ion Transport across Cell Membranes, in Subcellular Biochemistry: Alzheimer’s Disease – Cellular and Molecular Aspects of Amyloid. eds. Harris, R., Fahrenholz, F. Kluwer Academic/Plenum Publishers, London, UK (2004).

Colby D.W., Garg P., Chao G., Webster J., Messer A., Ingram V.M., and Wittrup K.D. Development of a Human Variable Light Chain Domain Intracellular Antibody against Huntingtin via Yeast Surface Display. J. Mol. Biol. Sep 17;342(3):901-12. (2004).

Webster J.M., Colby D.W., Ingram V.M., Wittrup K. D., and Messer A. Enhanced anti-Huntington’s Disease intrabodies. Abstract Soc. Neurosci., November 2004.

Blanchard BJ, Chen A, Stafford K, Weigele P & Ingram VM. Efficient Reversal of Alzheimer Fibril Formation and Elimination of Neurotoxicity by a Small Molecule. Proc Natl Acad Sci USA.Oct 5;101(40):14326-32. Epub 2004 Sep 23. (2004).

Works by or contributed to by Vernon M. Ingram on Book Gold Mine

• MIT Biology Hypertextbook (2006)