Searching the Main Actors Involved in Human Dementia

Project Summary

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.