My laboratory is focused on understanding aspects of the cellular and molecular biology underlying Alzheimer's disease (AD). The capacity to acquire and retain experiences is the foundation of nearly every aspect of human cognition. This disorder progressively and permanently disrupts memory-related functions until the identity of the victim is essentially erased.
Protein Processing in AD:
The pathological hallmark of AD is the florid deposition of senile plaques in the brain that are composed chiefly of the A-beta peptide. A-beta ranges in size from 39-43 amino acids in length and is derived from post-translational cleavage of the amyloid precursor protein (APP). A large body of evidence suggests that disturbances in the metabolism of APP and A-beta may be at the heart of AD pathogenesis. Some of the best evidence supporting this view comes from genetic studies showing that individuals inheriting mutations in APP develop early-onset AD. Remarkably, these mutations precisely flank the A-beta cleavage sites.
Recently, other evidence has emerged which further implicates APP metabolism as central to the Alzheimer's disease process. Mutations in Presenilin 1 and 2 (PS1 and PS2) have been identified that also cause early-onset AD. In these patients A-beta processing is altered to favor accumulation of a particularly amyloid-ogenic and toxic form of A-beta . These findings strongly suggest that, regardless of etiology, dysfunctional APP processing is a common feature of AD pathology.
Goals and Approaches:
The goal of this lab is to better understand the molecular mechanisms of A-beta biosynthesis and to elucidate how the presenilins influence A-beta generation. Much work remains to be done to understand these processes, particularly in neurons (the cell type most affected by AD).
To address these issues we make use of a novel human neuronal cell system (NT2N). NT2N neurons are derived from a teratocarcinoma cell line treated with retinoic acid to induce differentiation. Following differentiation and purification one is left with large cultures of pure (>99%), post-mitotic, human neurons that display mature axonal/dendritic polarity. This approach lends itself well to many neurobiological applications and because AD is essentially a human neuronal disorder, it is particularly well-suited for AD research. Primarily, the lab uses a number of virological approaches to express and study AD-related gene functions. These tools include recombinant, replication-defective Semliki Forest virus (SFV) and Vaccinia virus.
Using these approaches, we have recently discovered a novel intracellular pathway for the generation of A-beta localized in the endoplasmic reticulum. Currently, little known about the mechanisms governing accumulation of intracellular A-beta . Understanding these processes is a major thrust of this lab.
There is intriguing data to suggest that the presenilins may play a role in regulating intracellular calcium homeostasis. Thus, in addition to the A-beta processing studies outlined above, work is now underway to examine the effects of mutant presenilins on neuronal calcium regulation and plasticity.
The VA site has a critical mass of highly interactive laboratories focused on Alzheimer's disease research. These include the labs of: Drs. Gerard Schellenberg (genetics of neurodegenerative disorders); Thomas Bird (neurology and genetics of neurodegenerative disease); Suzanne Craft (glucose and insulin regulation in AD); Murray Raskind and Elaine Peskind (neuroendocrinology of stress-responsive hormone systems in normal aging and AD). This blend of both basic and clinically oriented research creates a particularly dynamic atmosphere that encourages creative new ideas.
Currently, there is no remedy for AD. Unfortunately the definitive cause(s) of AD have yet to be identified. One positive note is that any therapy capable of delaying disease progression for even 5 years would effectively be a cure for many individuals. Thus, one of the best hopes in fighting this significant public health problem lies with continued basic research aimed at understanding the fundamental biology of the cells affected by Alzheimer's disease.