Defining and Exploiting the Adaptive Immune Response During Neurodegenerative Diseases
Identifying the molecular origins of neurodegenerative diseases remains one of the most challenging scientific pursuits of our time. Understanding how Alzheimer's and Parkinson's disease are triggered in their earliest stages will lead to paradigm-shifting diagnostics and therapeutics. In order to gain insight into these devastating conditions, our laboratory is sifting through clues left behind by our immune system, which reacts to every injury—whether foreign or domestic— and develops a memory that protects us from future attacks. Thus, within us resides an indelible record of current and past illness in the form of memory B and T cells. “Reading” this record of injuries in patients with early stage neurodegenerative disease may provide clues into the origin of these chronic and devastating conditions.
One group of easily accessible "immune clues" are antibodies, which are secreted by B cells (Scheme 1A) and circulate throughout our bloodstream. To detect the disease-relevant antibody repertoire (shown in red in the scheme below), we can capture them from blood using the immune-provoking biomolecule that the antibody was raised against, called its cognate antigen. The antigen is recognized by the disease-specific antibody in the antigen-binding site (highlighted in red in the large IgG shown in scheme 1A) with exquisitely high affinity and specificity. However, when we do not know the identity of the antigen, or when we are searching for new antibody-antigen complexes, then we are unable to capture our antibody from the serum repertoire. Methods that do not rely on specific foreknowledge of the native antigen to detect disease-specific antibodies are better suited to uncover new pathways in diseases of unknown origin, and developing these approaches is a major focus of our laboratory.
Scheme 1. Overview of our chemical approach to target disease-relevant antibodies and applications thereof.
We take an unbiased combinatorial chemistry approach to uncover disease-relevant antibodies in patients with neurodegenerative disease. Using chemical synthesis, we create libraries containing millions of different combinations of chemical elements and screen for small molecules that bind with high affinity to the antigen binding sites of disease-specific antibodies (Scheme 1B). This small molecule is thus a surrogate for the native antigen and we no longer require the native antigen or knowledge of its composition to detect the disease-relevant antibody. With synthetic molecules as surrogates for the native antigen, we are no longer limited by the onerous physical properties of difficult-to-handle antigens, such as membrane-bound or multimeric proteins. Thus, the technology opens the door to performing chemical biology on otherwise intractable immune complexes.
Our lab is leveraging this screening platform to uncover diagnostic and therapeutic immune complexes in neurodegenerative diseases. In patients with Alzheimer’s disease (AD), we are applying our chemical screens to identify immune complexes present in patients who evade cognitive symptoms of the disease. We hypothesize that some patients have developed natural immunity to AD and discovering these antigens may prove valuable as therapeutics. We are also searching for diagnostic antibodies in patients with Parkinson’s disease (PD). Our hope is that these antibodies will lead to a simple blood test for PD at early stages of the disease, and provide new details into the cause and progression of this chronic disease.
Creating Selective Imaging Probes for Amyloidogenic Proteins
Amyloid aggregates are the hallmark pathological features of Alzheimer’s and Parkinson’s disease, and targeting these deposits has been a major focus of therapeutic and diagnostic development in recent years. Yet, despite overwhelming evidence suggesting that amyloid formation is the direct cause of neurodegeneration, targeting the principal components of disease plaques with therapeutics has failed to produce a drug capable of slowing or stopping the disease. Over recent years, it has become apparent that biological proteins do not simply transform from their native state into amyloid deposits. Before they mature into their distinguishable plaques, proteins that are capable of aggregating often form small aggregates called oligomers. Oligomers are not well characterized structurally because they are unstable, making them difficult to handle in the laboratory. Nevertheless, they are believed to play a far more insidious role in causing or exacerbating neurodegenerative disease than their plaque counterparts. Our laboratory is seeking to develop drug-like molecules that bind with high selectivity to specific conformations, or "shapes", of amyloid oligomers. We believe that targeting these species with molecular precision will enable the development of: 1) superior biomarker assays for disease progression; 2) much-needed therapeutic paradigm shift; and 3) chemical probes to test the amyloid cascade hypothesis.
To achieve our objective, we are developing combinatorial synthesis and screening methods that allow us to engineer small molecules that can target the most intractable pre-amyloid aggregates with high selectivity. We combine a host of biophysical techniques to target biologically important pre-amyloid conformers. Our approach is to screen drug-like molecule libraries in an unbiased fashion to identify non-perturbative ligands of toxic oligomers of pre-amyloid oligomers. This involves performing sequential counter screens to make sure our ligands do not interact with benign conformations of amyloid proteins. Hit compounds are then fashioned into effector pharmacophores using many of the effector conjugates available in the chemical biology toolkit.
Characterizing Novel Oxidative Cellular Processes in the Aging Brain
Oxidative stress is an unavoidable consequence of aging that affects many facets of cellular function and regulation. Products of oxidative stress are ubiquitous, and can be seen affecting immune regulation, proteostasis and energy metabolism, just to name a few. The consequences of oxidative damage are both central and profound to human aging, and a breakdown in our cell’s ability to regulate oxidative damage has been alleged to play a causative role in neurodegeneration. Therefore, detecting products of oxidative stress is a strategy for diagnosing neurodegeneration and to help inform methods to reverse oxidative damage.
We are developing chemical and biological tools to detect and trace indicators of oxidative damage in the aging brain. Our objectives are to define pathways and products of oxidative stress present during aging and neurodegeneration. Diagnostic tests based on these products will serve as indicators of Alzheimer’s and Parkinson’s disease progression. Ultimately, we wish to develop “anti-oxidant” strategies to reverse the most damaging oxidative products and slow the course of aging and neurodegeneration that is exacerbated by oxidative metabolism.