Zaffaroni Alzheimer’s Disease Translational Research Projects

Round 1, Zaffaroni pilot research project 1

Principal investigator: Katrin I. Andreasson, MD

Targeting TREM1-TREM2 immune signaling in Alzheimer’s disease

There are no preventive or disease-modifying treatments for Alzheimer’s disease, and strategies to lower levels of amyloid-beta peptides have not yet shown clinical benefit in large Phase III trials. Alternative approaches should be pursued, which target novel pathways in the pathobiology of Alzheimer’s disease. TREM1 (Triggering Receptor Expressed on Myeloid cells-1) is a unique membrane receptor that potently amplifies inflammatory responses. Activation of TREM1 leads to immune responses that injury nearby cells. Our studies in experimental models of Alzheimer’s disease show that levels of TREM1 are reduced in brain immune cells and show that TREM1 contributes to disease progression in these models. In our research, we will identify a series of candidate small molecules that are able to inhibit TREM1 function. The long term objective is to develop treatments that target the TREM1 immune response in the brain in order to slow or halt the development of Alzheimer changes.

Round 1, Zaffaroni pilot research project 2

Principal investigator: Isabella A. Graef, MD

Evaluation of the transthyretin stabilizer AG10 in Alzheimer’s disease

Several studies show genetic and biochemical interactions between Aβ and transthyretin (TTR). TTR is a transport protein that modulates Aβ aggregation and deposition in vitro and in vivo. In a mouse model of Alzheimer’s disease, stabilization of TTR with a non-steroidal anti-inflammatory drug decreases Aβ deposition and improves cognition. Hence, TTR stabilization may be a novel way to alter the deposition of Aβ. This effect might in turn delay the progression of Alzheimer pathology. To treat Alzheimer’s disease in humans, one would want a highly specific, orally bioavailable TTR stabilizer, which can penetrate the blood-brain-barrier. However, most chemical compounds that bind TTR also bind many other targets. Tafamidis is an exception. This TTR ligand is being studied in clinical trials to treat other forms of TTR-mediated amyloidosis. Tafamidis, however, does not cross the blood brain barrier. My lab has developed a potent, highly specific TTR stabilizer, AG10, which is predicted to cross the blood brain barrier. If so, it would be a strong candidate to stabilize TTR in the brain. In studies of this proposal, we will test whether the oral administration of AG10 affects the development of Alzheimer-like pathology in vivo.