Research Summary

Investigating the role of intracellular calcium signal remodeling in the pathogenesis of Alzheimer's disease

Alzheimer’s disease (AD) is one of the most catastrophic fatal diseases that is marked by severe cognitive disability leading to a decline in physical function. The molecular mechanisms that lead to the accumulation of β-amyloid in the brain that characterizes the pathological state are not yet clear. A rare familial form of AD which is caused by mutation in the gene that encodes presenilin (PS) has provided a valuable window in its pathogenesis. PS is an integral Endoplasmic Reticulum (ER) protein that is involved in the production of β-amyloid. Separately AD related mutation in PS is seen to disrupt intracellular calcium dynamics. Calcium is a key signaling molecule in synaptic transmission that finely orchestrates synaptic plasticity mechanisms directly involved with memory formation and deletion. Remodeling of the calcium signal has been identified as the earliest pathogenic event that could be the basis of cognitive dysfunction seen early on in AD.

Our approach is to use a biophysically detailed spatially explicit computational models to
investigate the role of the molecular pathways that have been implicated in modifying the calcium signal as seen in inherited AD. The goal is to quantify the chronology of events that begin with short term changes in synaptic transmission and lead up to defects in Long Term Potentiation and Long Term Depression, thought to be the cellular underpinning of memory.

Since the decline in mental function precedes the typical structural changes defined by plaques of beta amyloids, this line of investigation can provide valuable insights into the pathogenesis of the disease.

Figure Legend: Computational model of a CA3-CA1 synapse reconstructed from serial electron microscope images: Shown here is the axonal terminal of the CA3-CA1 synapse that makes an 'en passant' synaptic contact(postsynaptic terminal not shown). The CA3-CA1 synapse is a small synapse in the hippocampus thought to be crucially involved learning and memory. It has a single active zone with approximately 7-8 vesicles ready to be released (docked vesicles). The Reticulum (ER) serves as an intracellular source of calcium apart from voltage dependent calcium channels (VDCCs), that can be tapped by the opening of Inositol Triphosphate Receptors (IP3R) or Rynodine Receptors (RyRs). The SERCA (calcium pump on the ER) and the PMCA (calcium pump on the plasma membrane) work to keep calcium concentration in the cytosol to ~ 100 nM. The calcium concentration in the ER and the extracellular space is high (~200 µM and 2 mM respectively). The computational model describes some of the key pathways implicated in the disruption of intracellular calcium signaling seen in an inherited form of Alzheimer's Disease. Reconstruction credits: Edward Ennedy, Salk Institute, Thomas Bartol, Salk Institute and Kristen Harris, University of Texas Austin.