Lab Research

The ADRC's support of both clinical and laboratory studies represents a critical link in what is termed "translational" research. Translational research refers to the ability of both laboratory and clinical researchers to use each other's findings in a practical and reciprocal manner that is of most immediate relevance to patients. Below is a selection of some of the important laboratory studies currently underway at Mount Sinai.

Project 1. Misprocessing of Multiple Peptides in Common Forms of Alzheimer’s Disease

Sam Gandy, MD, PhD, Project Leader
Patrick Hof, MD and Dara Dickstein, PhD, Co-Project Leaders

When nerve cells communicate, small substances called neurotransmitters and peptides convey the signals from one cell to the next cell in the circuit. The above figure shows a communication point between two nerve cells called a synapse; the tiny circles in the figure are the peptides. At least one of these peptides, known as the amyloid-beta peptide, forms abnormal clumps inside these synapses causing them to break down and communication to fail.

We have discovered that another peptide, known as alcadein, is also mismanaged at the synapse in Alzheimer’s Disease. We believe that a common upstream mechanism, known as gamma secretase, malfunctions in Alzheimer’s Disease, causing both the change in amyloid metabolism and alcadein metabolism. We are studying this in human brain and mouse models.

Project 2. Inflammation and AD Progression

Takeshi Sakurai, MD, PhD and Joseph Buxbaum, PhD, Co-Project Leaders

Inflammation is believed to accelerate the progression of AD and a consequence of gamma-secretase activation is alterations in gene expression patterns in the brain, disrupting mechanisms that are protective against inflammation. Such processes lead to increases in a brain-tissue destructing enzyme, called caspase-4, which is found only in primates. We have developed a mouse model that expresses human caspase-4 and are studying in this mouse model its involvement in AD progression as well as in human postmortem brain samples. We are also clarifying other genes that accelerate AD progression, in addition to caspase-4.

Project 3. Impaired Angiogenesis in Alzheimer’s Disease

Anastasios Georgakopoulos, PhD, Project Leader
Nikolaos K. Robakis, PhD, Co-Investigator

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by severe neurovascular dysfunction. Presenilin-1 (PS1) is a protein of central importance to the neuropathology of AD. It controls the proteolytic cleavage of many proteins via an enzymatic activity called γ-secretase. We found that PS1/γ-secretase regulates the cleavage of ephrinB proteins and their EphB receptors. These proteins are expressed in both endothelial and neuronal cells and are critical for the structure and function of blood vessels in the brain.

It is known that ephrinB stimulates angiogenesis. The cleavage of ephrinB by PS1/γ-secretase produces a peptide called ephrinB/CTF2. This peptide promotes outgrowth of processes in endothelial cells suggesting that PS1/γ-secretase may regulate endothelial cell physiology and therefore the integrity of blood vessels in the brain. Mutations in PS1 found in Familial Alzheimer’s Disease (FAD) inhibit the cleavage of ephrinB indicating a malfunction of γ-secretase in FAD.

These observations raise the possibility that these mutations may also inhibit the ability of ephrinB to induce angiogenesis. The figure shows the interaction of the ephrinB proteins with their EphB receptors in two opposing endothelial cells, as well as some of the signaling events that are stimulated in both cells, by this interaction leading to various cellular functions including angiogenesis. We study the role of the PS1/γ-secretase system in the ephrinB-mediated angiogenesis in the brain and the possible consequences that the malfunction of this system may have on brain angiogenesis in AD.

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