Cure Alzheimer's Fund: Targeting Breakthrough Research

There is general agreement that beta amyloid (Aβ) is a likely causative agent in the development of Alzheimer’s disease. There is growing evidence that early in the disease an important target of Aβ is the synapse, the site of communication between neurons. We have found that exposure of synapses to Aβ causes their weakening. In this proposal we will examine the role played by PICK1, a protein that associates with synaptic receptors and participates in the weakening of synapses by Aβ.

Stem cells are the least mature cells in the body. Because these cells are so immature, they can be treated with a defined cocktail of factors and, depending on which factors are used and in what sequence, those factors can cause maturation of cells along discrete cell types. With a new tool called induced pluripotent stem cells, it now is possible to take skin cells from adults and return them to this immature state. By redirecting skin cells from Alzheimer’s patients and turning them into nerve cells, we are able to study adult Alzheimer’s neurons (nerve cells) in the lab.

We will carry out Whole Genome Sequencing (WGS) of all subjects in the National Institute of Mental Health (NIMH) Alzheimer’s disease family sample (1,510 subjects; 437 AD families). We will identify functional DNA variants throughout the human genome that are inherited as risk factors for Alzheimer’s disease. We also will analyze DNA from brain samples of subjects who exhibited significant Alzheimer’s pathology at autopsy, but never suffered from dementia; this will allow us to identify protective gene variants as well.

The goal of this project is to identify a series of highly potent gamma-secretase modulators able to lower Abeta₄₂ and Abeta₄₀ production while concomitantly increasing the less toxic production of Abeta₃₈ without measurably affecting gamma-secretase-mediated processing of the Notch 1 receptor (which is very important in a variety of cellular processes for cell-to-cell communication).

Many lines of evidence suggest that beta-amyloid peptides cause neuronal damage and affect fundamental memory processes early in the course of Alzheimer's disease (AD). Two membrane-associated enzymes, namely betasecretase (BACEl) and gamma-secretase are responsible for beta-amyloid production. Understanding the details regarding the cellular and molecular mechanisms involved in beta-amyloid production in neurons is a topic of central importance in molecular AD research.

The goal of this project is to test the hypothesis that desflurane is a safer anesthetic than isoflurane for AD patients in order to find safer anesthetics that won’t worsen AD symptoms.

The goal of this project is to collaborate with a medicinal chemist to design, synthesize and test the efficacy of third-generation small molecules that will activate glial receptors. The most efficacious molecules then will be tested for their ability to reverse plaque burden in mouse models of Alzheimer’s disease.

PICALM, the gene encoding phosphatidylinositol binding clathrin assembly (picalm) protein, plays a key role in endocytosis, a process which regulates the function of cell receptors and synaptic transmission. PICALM is one of the most highly validated Alzheimer’s disease (AD) risk factors. Its role in AD, however, is unknown. A recent genome-wide screen for modifiers of amyloid-b peptide (Aβ) toxicity in yeast has identified the key role of the yeast homologue of PICALM.

Recent studies from the laboratory of Dr. Gary Landreth (Cramer P. et. al (2012) Science 335) have demonstrated that Bexarotene (Targretin), a highly selective, blood-brain barrier-permeant, FDA-approved, RXR agonist for the treatment of cutaneous T-cell lymphoma, can rapidly reduce amyloid plaque burden and rescue behavioral deficits in transgenic mouse models of AD.