Johns Hopkins Medicine

Alzheimer's Disease Research Center

Neuronal activity-dependent secretion of A-beta and immediate early genes

Principal Investigator: Paul Worley, M.D.

Arc is an immediate early gene that is transcriptionally induced in response to forms of neuronal activity that underlie learning and memory. The overarching goal of the study is to examine the molecular mechanisms that underlie activity-dependent secretion of the amyloid beta (A-beta) peptide and to examine their potential impact on synaptic dysfunction in Alzheimer's disease (AD). There are four specific aims:

Aim 1: To examine the cellular basis of Arc-dependent A-beta secretion. We will test the hypothesis that Arc enhances the processing of amyloid precursor protein (APP) by gamma secretase in recycling endosomes. We will examine the model that Arc enhances A-beta generation by recruiting gamma secretase, either from the plasma membrane or intracellular endosomes, to endosomes that traffic APP from the plasma membrane.

Aim 2: To examine the hypothesis that Arc binding to presenilin 1 (PS-1) is essential for Arc-dependent A-beta generation. We will define regions of Arc and PS-1 that are necessary and sufficient for binding. As part of this analysis, we will identify peptides that can selectively block their interaction and we will test if these peptides can interrupt activity-dependent generation of A-beta in primary neuronal cultures.

Aim 3: To examine the hypothesis that Arc contributes to A-beta generation and plaque deposition in vivo. These studies will monitor the age and gender dependence of soluble and insoluble A-beta40/A-beta42 and plaque deposition in transgenic mice known as APPswe/PS1ΔE9/Arc+/+ mice compared with APPswe/PS1ΔE9/Arc-/- mice.

Aim 4: To examine expression of Arc and associated proteins in the brain tissue of cognitively normal and cognitively impaired individuals. Preliminary studies indicate that Arc protein is up-regulated in the brains of patients of AD. We will determine if this is consistent across a larger group of subjects and assess the association with amyloid plaques and with dementia severity.

For more information, contact Paul Worley at pworley@jhmi.edu.