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Hartley
Dean
M.
PhD, MS, BS
Associate Professor
Novel Clinical and Translational Methods Core
Neurological Sciences
Graduate College
1735 W. Harrison St.
Cohn Research Building
Ste. 316
Chicago, IL 60612

1735 W. Harrison St.
Cohn Research Building
Ste. 336
Chicago, IL 60612

(312) 563-3599
(312) 563-3571
dean_hartley@rush.edu
PhD, Stanford University, Standford, Calif.,1991
MS, University of Illinois, Urbana Ill., 1981
BS, University of Illinois, Urbana Ill., 1978

Biological Phenomena Cell Phenomena and Immunity, Biological Sciences, Genetic Processes, Mental Disorders, Nervous System Diseases, Pathological Conditions Signs and Symptoms, Physiological Processes
Animal Pharmacology, Animal surgery/Modeling, Antibody Production, Chromatography, Electrophysiology Cell/in vivo, Electrophysiology/EEG, Gene Transfection, Imaging Techonology, Immunohisto-/immunocytochemistry, Laser Capture, Microscopy (Electron Transmission Fluorescence Confocal), Patch Clamp/Individual Channel Recording, Tissue Culture (Primary, Cell Line), Ultra centrifugation techniques

The focus of the Hartley laboratory is on mechanisms initiating neuronal dysfunction and injury in neurodegeneration, with specific emphasis on the molecular pathogenesis of Alzheimer's disease. Many neurological disorders start as very subtle phenotypes, suggesting that the disease process may start many years before clinical symptoms appear. We are interested in these preclinical states to pinpoint when the disease begins, allowing us to understand the events initiating this process. By identifying this important window, specific therapeutic strategies and more accurate tests can be developed to determine those at risk, allowing potential therapies to be administered as early as possible. Rush has excellent clinical and research expertise in AD, providing a true bench to bedside program through the Neurological Sciences Department and Rush's Alzheimer's Disease Center. Specifically, my laboratory is focused on identifying early markers of brain dysfunction in neurodegeneration by using a wide variety of techniques, including biochemical and biophysical techniques to understand protein aggregation, imaging techniques to understand how subtle morphological alterations alter function, electrophysiological techniques to monitor neuronal function, as well as genomic and proteomic techniques to understand the initiation of the disease process. Additionally, we are interested in developing knowledge based systems to help in organizing and exploring the relationships of related concepts needed to initiate and expand new research ideas.

Specific Research Questions:

When does Ab aggregation occur? Ab as the causative agent in AD is the leading hypothesis, which is dependent on the abnormal folding of Ab and its aggregation. We do know that aggregation occurs in the AD brain by the fact that plaques, a hallmark of AD, are composed of Ab fibrils (i.e. aggregated Ab). However, as important as this hypothesis is, we know very little about when it occurs and how this process occurs. Identifying the initiation of the process is critical in determining if Ab initiates the disease process or is a secondary event in AD pathogenesis. Currently, we are investigating the presence of abnormal Ab folding in the early stages of AD. To do so, our research is taking advantage of the unique Rush Religious Orders Study (RROS) to obtain human tissues to ascertain the type and quantity of Ab from pathologic tissues and age-matched controls. A very important aspect of RROS is the cataloging of tissues at different time periods during normal and pathologic aging, especially capturing individuals early in the disease. Our investigation is centered on populations of patients that have significant memory problems and have recently been identified in the RROS and other studies to be very early AD or having a precursor to the disease. Although this group of patients does not fit the classic definition of AD due to their lack of dementia, they have a significant deficit in episodic memory with the possible impairment of other cognitive domains and are referred to as mild cognitively impaired (MCI). Patients with specific episodic memory problems in conjunction with mild cognitive impairment have high conversion rates to AD, indicating they represent an early stage of AD. Studying these early stages may give us an opportunity to understand the initiation of AD. If Abeta assemblies are important in the initiation of AD, then these tissues from patients with episodic memory problems or mild cognitive impairment should represent an important stage in determining if Ab aggregation has occurred and the nature of the aggregates formed. These early clinical stages are being studied in context of both normal, aged matched controls and clinically diagnosed AD cases available through the RROS. Ab aggregates are currently being isolated, characterized and assessed as to how these various assemblies correlate with neurological status cataloged for each patient. Because there have been no studies systematically studying Ab assemblies from human material, it has been difficult to determine if the Ab species in AD mouse models reflect what is occurring in human tissues. Therefore, Ab is being isolated from different ages of AD mouse models and compared to human Ab assemblies isolated from the RROS tissues. This understanding will be important in helping us determine the validity of the mouse model, which is a critical component for developing human therapeutics.

What factors influence Ab aggregation? Evidence suggests that protein aggregation and its subsequent accumulation are common factors in the pathophysiology of many of the neurodegenerative diseases, including AD. In vitro studies have shown that Ab can undergo self-directed protein aggregation, forming protofibrils. Unfortunately, how Ab aggregation is initiated in vivo is still unknown, especially in light of the fact that in vitro Ab self-aggregation requires concentrations 100-1000 fold greater than that observed in the AD brain. Interestingly, only certain regions of the brain show evidence of aggregation, suggesting that specific factors play a role in initiating or preventing aggregation. We are interested in identifying these endogenous factors to understand this process, as well as to control or block the aggregation.

How do soluble aggregates of Ab alter neuronal function? For unknown reasons the amyloid beta-protein undergoes aggregation in the AD brain and these conformational changes are thought to be key to imparting its toxicity and the initiation of the disease. Because the earliest changes associated with clinical symptoms are memory loss and cognitive impairment, it suggests that changes are occurring at or alter brain synapses. For these reasons, electrophysiological studies have been used to understand synaptic changes and these studies have found that different aggregation states selectively alter ion channels. Our studies have included the use of whole-cell patch clamp techniques to investigate Ab interaction with specific channels. Additionally, we have employed extra-field recording to monitor Ab effects on long term potentiation, a cellular model of learning and memory. These techniques are some of the most sensitive readouts to understand amyloid beta-protein interactions with neurons and may help to establish the first pathological events in initiating AD.

Can Ab aggregates of different sizes alter neuronal morphology, which ultimately manifests as changes in neuronal function? The fact that AD is a progressive disease first expressed clinically as a very mild and slowly progressive cognitive and amnestic disorder suggests that neuronal/synaptic changes may occur early in the disease, prior to cell death. One of the early structural changes that could have functional consequences is discrete synaptic alteration. Our laboratory is interested in changes in neuronal spine shape and/or number, changes in neurite number or length and changes in neuronal shape or pruning of neuronal processes; the latter change could be just as detrimental to brain function as complete loss of the neuron. We are interested in the biochemical and molecular underpinnings that can drive the progressive degeneration, starting as subtle changes in the axons and dendrites and culminating in the destruction of the neuron. Understanding these processes will help us devise new therapeutic strategies to slow or stop this progressive degeneration.

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