Searching the Main Actors Involved in Human Dementia

Dolores Del Prete, PhD
Albert Einstein College of Medicine (Bronx, NY)
Year Awarded:
2013
Grant Duration:
July 1, 2013 to June 30, 2015
Disease:
Alzheimer's
Award Amount:
$100,000
Grant Reference ID:
A2013046F
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern

Searching the Main Actors Involved in Human Dementia

Mentors

Luciano D'Adamio, MD, PhD
Albert Einstein College of Medicine (Bronx, NY)

Summary

Mutations in genes that regulate the processing of the APP protein (the source of Abeta protein) cause early-onset Familial Dementias (FD) in humans. BRI2 is one of these genes. Dr. D’Adamio’s team has generated a mouse model that faithfully represents the human dementias caused by the mutation in BRI2. In this model, APP processing is increased, and leads to memory loss. Given the fact that these mice mirror the genetic defects of patients, they are ideal to dissect the mechanisms that cause dementia in humans. Therefore, this model is suitable for testing therapies for human dementias, including Alzheimer’s disease. In addition, Dr. Del Prete’s studies proposed in this grant application will serve as a preliminary assessment of BRI2-like drugs that could reduce abnormal APP processing without inhibiting the other proteins that mediate the normal processing of APP.

Details

Alzheimer’s disease (AD) is the most common type of dementia that is clinically characterized as having progressive cognitive deterioration, including loss of memory, reasoning, and language. Mutations in genes that regulate the processing of APP protein cause early-onset Familial Dementias (FD) in humans. All APP disease-causing mutations are located either in the Abeta sequence or near a cleavage site which influences APP processing by different mechanism. Dr. D’Adamio’s team has generated a mouse model that faithfully represents the human dementias caused by the mutation of BRI2 (called FDDki mice). These mice accurately represent the genetic defects of patients and show an increased APP processing, that leads to memory loss.

The aim of this project is to analyze the domains or fragments of APP involved in the development and progression of disease in FDDKI mice. Dr. Del Prete will study the role of APP processing using genetic and biological approaches. Then, there will be further characterization of the mechanisms by which APP processing and APP-derived metabolites mediate memory deficits in FDDKI mice. The finding that the neurological symptoms of FDDKI mice require the abnormal processing of APP, suggests that this model will help to uncover the disease pathways associated with AD.

The innovation of this research is that the experiments don’t rely on Abeta peptide being the ultimate disease-causing protein; it’s the assessment of all domains or fragments of APP to see if they’re involved in causing disease in FDDKI mice. The ultimate goal is to use the discoveries to develop non-amyloid based targets for therapeutic strategies to produce disease-modifying AD drugs.

About the Researcher

Dr. Del Prete is a research fellow in the laboratory of Professor Luciano D’Adamio at Albert Einstein College of Medicine. She completed her Ph.D. in the Italian institute of technology, department of neuroscience and brain technologies (NBT) headed by Prof. Fabio Benfenati, and then in the laboratory headed by Dr. Frédéric Checler (Institute of Molecular and Cellular Pharmacology, Valbonne, France).

Dr. Del Prete focused her studies on evaluation of the role of calcium signaling in Alzheimer disease observing that blocking the calcium release decreases levels of b-amyloid (Ab) and cognitive deficits associated with the disorder.