Structure of Toxic Particles of the Alzheimer's Disease Peptide

Peter M Tessier, PhD
Rensselaer Polytechnic Institute (Troy, NY, United States)
Year Awarded:
Grant Duration:
July 1, 2011 to January 31, 2014
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Northeastern

Structure of Abeta C-Terminal Domain in Toxic Oligomers


The seminal event in Alzheimer's disease is the misfolding and clumping of a protein fragment into small particles that are highly toxic to brain cells. Why such peptide particles are toxic, while other particles composed of the same peptide are non-toxic, is one of the key unanswered questions in Alzheimer's disease research. We seek to explain the structural differences between toxic and non-toxic peptide particles with the long-term goal of guiding the rational design and development of new therapeutics to treat Alzheimer's disease.


A protein called amyloid precursor protein (APP) can be cut into toxic and non‐toxic forms of beta‐amyloid. The toxic forms of beta‐amyloid (called beta‐amyloid 42) misfold and clump together into brain plaques, a hallmark of Alzheimer's disease. Other beta‐amyloid fragments of APP do not misfold. Dr. Peter Tessier and collaborators will use new detection methods to study the differences between toxic and non‐toxic folding of beta‐amyloid proteins in Alzheimer's disease. Their long term goal is to design a drug that could prevent this folding and clumping. If successful, this method could be applied to toxic misfolding that happens in other neurodegenerative diseases, like Parkinson's disease, Huntington's disease, and Prion disease (including Creutzfeld‐Jacob or “Mad Cow” disease).

Research Updates

The seminal event in Alzheimer’s disease is the clustering of sticky protein fragments into small particles that are toxic to brain cells. Dr. Tessier’s team is basing their project on their recent discovery that the Alzheimer’s protein can form two types of particles of identical size, yet only one of them is toxic to brain cells. In the first year of this study, the team has developed new methods for investigating the structure of both types of protein particles to understand why only one type is toxic. They find that the stickiest regions of the Alzheimer’s protein are exposed on the surface of the toxic particles, while these same regions are shielded within the core of the non-toxic particles. Moreover, they find that the toxic Alzheimer’s particles are unusually effective at disrupting “membranes” (the packaging that keeps cells intact) that are similar to the outer wall of brain cells, while non-toxic particles are unable to disrupt such membranes. Dr. Tessier’s team suggests their results show that toxic Alzheimer’s particles have sticky surfaces that are able to interact with and disrupt brain cells, leading to cell death and loss of brain function. They expect that the methods they have developed for studying the structure of Alzheimer’s protein particles will be useful for identifying toxic particles in many other scientific studies of Alzheimer’s disease. Moreover, their findings suggest that drugs targeting the sticky patches of the Alzheimer’s protein may be most effective at preventing the toxicity of Alzheimer’s protein particles.

About the Researcher

Dr. Peter Tessier is an assistant professor of Chemical & Biological Engineering at Rensselaer Polytechnic Institute. Tessier joined the Rensselaer faculty in 2007 following an American Cancer Society postdoctoral fellowship at the Massachusetts Institute of Technology's Whitehead Institute for Biomedical Research. He received his bachelor's degree in chemical engineering from the University of Maine and went on to earn his doctoral degree in chemical engineering from the University of Delaware. His research aims to understand the misfolding of proteins into toxic protein particles in Alzheimer's disease and related disorders with the long-term goal of preventing, reversing, or redirecting this deleterious misfolding behavior.


Rational design of potent domain antibody inhibitors of amyloid fibril assembly. Ladiwala AR, Bhattacharya M, Perchiacca JM, Cao P, Raleigh DP, Abedini A, Schmidt AM, Varkey J, Langen R, Tessier PM. Proc Natl Acad Sci U S A. 2012 Nov 15. PubMed Icon Google Scholar Icon

Ladiwala, A.R, Litt, J., Kane, R.S., Aucoin, D.S., Smith, S.O., Ranjan, S, Davis, J., Van Nostrand, W.E., Tessier, P.M., "Conformational differences between two amyloid â oligomers of similar size and dissimilar toxicity", J. Biol. Chem., in
press (2012). PubMed Icon Google Scholar Icon

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