Ehud Cohen, PhD
Lecturer
The Hebrew University of Jerusalem

Roles of Peptidylprolyl Cis/Trans Isomerases in the Regulation of Aging and Countering Alzheimer's Disease

Most neurodegeneration that has a familial mutation-link occurs in a person in their 40s, while most nonhereditary cases occur in people beginning in their 60s or later. Why neurodegenerative disorders emerge late in life and why distinct disorders share common temporal patterns are unsolved enigmas. Recent studies show that an aging process enables the onset of these maladies by actively suppressing mechanisms that protect the young organism from disease. Chaperones - the proteins that ensure the correct folding of other proteins and prevent them from aggregation - play key roles in this process. Since human neurodegeneration often stems from uncontrolled protein aggregation, the activity of folding chaperones is thought to be critical for disease prevention early in life. One group of folding chaperones that might be involved in protecting the young organism is called cyclophilins. Dr. Cohen's research will focus on the possible roles of cyclophilins in preventing Alzheimer's disease (AD) from emerging early in life and will test how this activity is affected by aging. His research could answer the question of whether the maintenance of cyclophilin activity through late life could protect against developing AD and will help unearth the mechanisms underlying the onset of some types of familial AD.

Raquel L. Liberman, PhD
Assistant Professor
Georgia Tech

Crystal Structure of an Intramembrane Asparyl Protease

Presenilin is a critical component of a large enzyme complex that plays a key role in producing, from a precursor protein, the range of peptides (strings of amino acids) that form the amyloid substances found in plaques, blood vessels and neurons of the brains of patients with Alzheimer's disease (AD). This complex is very challenging to study by methods that would allow its atomic structure to be revealed. Dr. Lieberman's research will focus on the discovery of the atomic structure of an enzyme in the same family as presenilin. To accomplish this, she will produce the model enzyme using recombinant DNA technology, purify it by column chromatography, grow crystals of the enzyme and then use the crystals to collect X-ray diffraction data, creating a three dimensional molecular structure. By studying the structure of the related model protein, which can work independently to produce similar peptide fragments, she will better understand the chemistry behind how the presenilin complex cleaves the amyloid precursor protein to form amyloid peptides. With an experimentally-determined three-dimensional atomic structure of an enzyme capable of producing amyloidogenic peptides, she will gain tremendous insight into its biochemistry and function. The results can lead to new experiments in vitro, in cells, and in animals to better understand the role of peptide cleavage in AD, thus offering new ways to approach treatments to control amyloid peptide formation in AD patients.

Gad A. Marshall, MD
Instructor in Neurology, Associate Neurologist
Brigham and Women's Hospital

Amyloid Deposition and Frontally Mediated Symptoms in MCI

Patients with mild cognitive impairment (MCI), often a precursor to Alzheimer's disease (AD), may present with apathy (loss of interest, lack of motivation and social withdrawal) and executive dysfunction (impairment in complex attention, working memory, organization, and reasoning) that leads to impairment in instrumental activities of daily living (IADLs). IADL impairment includes difficulties in preparing meals, handling finances, using transportation, shopping, and many other everyday activities. Symptoms of MCI are thought to be caused by dysfunction in the frontal regions of the brain. Recent advances in brain imaging now allow tracking of amyloid development, thought to be a main cause of AD. The goal of Dr. Marshall's research is to understand the biological underpinnings of apathy and executive dysfunction in relation to IADL impairment in MCI and mild AD, focusing on amyloid deposition and frontal and parietal nerve cell connection dysfunction. This could improve the clinical characterization of MCI subjects for clinical trials and develop more sensitive tests for disease progression. It may also offer the opportunity to differentiate between patients whose MCI will progress to AD and intervene with disease-modifying agents targeting amyloid, thus attacking the disease at its earliest stages.

Esther Oh, MD
Assistant Professor
Johns Hopkins University

Oral Glucose Tolerance Test For Alzheimer's Disease Biomarker Development

Measuring amyloid levels in the cerebrospinal fluid (CSF) may be a useful way to identify people who have Alzheimer's disease but is difficult to obtain because the procedure is invasive. A much less invasive method - a simple blood test - has not been shown to consistently link blood amyloid levels with levels of cognitive function and disease stage. The goal of Dr. Oh's research is to modify the amyloid blood test so that it may be able to determine whether someone has early forms of Alzheimer's disease (AD) or predict who may develop the disease among individuals who have certain forms of mild cognitive impairment (MCI). Dr. Oh will confirm and extend earlier results that have shown that a simple oral glucose tolerance test that has been shown to produce short term increases in the blood levels of a particularly toxic form of amyloid, is not so altered in patients with AD and MCI. Moreover, she will seek evidence of a proposed mechanism for how this occurs, one that is thought to involve changes in the release of a substance that can modulate the action of insulin. Since many cases of AD are diagnosed at more advanced stages, the diagnostic blood test, which could predict the likelihood of a person developing AD years in advance, could allow clinicians greater opportunity to intervene when drug therapy is likelier to be more effective. Also, since many treatments are targeted at lowering or clearing the amyloid proteins from the brain, this modified amyloid blood test might provide a means of monitoring the effects of treatment.

Lucia Pastorino, PhD
Instructor in Medicine
Beth Israel Deaconess Medical Center

Role of the Prolyl Isomerase Pin1 in the Modulation of PS1 Activity

Proteins regulate the activity, the physiology, and the life of the cell. They exist as three dimensional structures that can undergo changes in their spatial conformation. One could imagine proteins as balls of wool (as it exists in its normal folded state), together with strings that stretch out of it, representing distinct regions of the protein. In the normal maintenance of the cells, the way these strings are oriented in the space (protein conformation) may be changed by other proteins. These conformational changes impact the protein activity, and this results in up-regulation or down-regulation of certain functions crucial to keeping the cell functioning normally. In this project, Dr. Pastorino will investigate how the regulation of protein conformation may be crucial in the development of Alzheimer's disease. Specifically, Dr. Pastorino will investigate whether Pin1, a protein that regulates the spatial conformation of other proteins, modifies the functional activity of presenilin 1, known to be key to the generation of damaging fragments (amyloid peptides) derived from a larger precursor protein. These amyloid peptides are associated with the typical pathology seen in the brains of patients with Alzheimer's disease.

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