2006 Awardees

Investigator: Brandon Ally, PhD
Project Title: Activation in the Posterior Association Cortex as a Therapeutic Marker

Finding a reliable and cost-effective measure to determine a patient’s response to a memory-enhancing medication could help clinicians know which patients are responding to a particular drug, in addition to providing new clinical outcome trial measures that can be used in novel drug discovery. This proposal will determine whether a component of the event-related potential (ERP) waveform associated with episodic memory performance can be used as a physiologic measure of response to drug therapy in early Alzheimer’s disease (AD). Enhanced memory performance is indicated by a robust activation in the posterior association cortex (PAC) of the brain. This area is of special interest as recent research suggests that the earliest AD pathology may occur in the PAC.  The aims of this project are twofold: (1) to determine whether the activity in the PAC is improved with cholinergic therapy in patients with mild AD, and (2) to determine whether enhanced activity in the PAC from cholinergic therapy correlates with improvement on standard neuropsychological tests of cognitive function in patients with mild AD.

Investigator: Isabel Carreras, PhD
Project Title: Relationship between Clusterin and Abeta Aggregation in a Mouse Model of AD

The pathogenesis of Alzheimer’s disease (AD) is not fully understood and no effective treatment is currently available. AD causes a progressive decline in cognitive function and is pathologically characterized by the accumulation of extracellular senile plaques that contain the amyloid beta peptide (Aß) in the form of amyloid fibers, and intracellular neurofibrillary tangles composed of filamentous aggregates of hyperphosphorylated tau protein. Compelling evidence suggests that the pathological accumulation of Aß is the primary cause of AD and that other pathologies are downstream consequences however, cognitive decline in AD does not correlate with senile plaque burden. In vitro studies with clusterin (apoJ), a chaperone protein associated with HDL and found in senile plaques, led to the discovery that soluble Aß oligomers may represent the initial and predominant neurotoxic species of Aß in AD. Using a recently developed oligomer-specific antibody, this study aim to explore the role of clusterin in the process of Aß oligomerization and fibrillarization in a triple transgenic model of AD (3xTg-AD) that progressively develops Aß and tau pathologies.

The project resulted the peer-reviewed publication listed below.

McKee AC, Carreras I, Hossain L, Ryu H, Klein WL, Oddo S, LaFerla FM, Jenkins BG, Kowall NW, Dedeoglu A. Ibuprofen reduces Abeta, hyperphosphorylated tau and memory deficits in Alzheimer mice. Brain Res., 2008;1207:225-36.