Alzheimer disease (AD) pathology is characterized by beta-amyloid (A?) plaques and tau-containing neurofibrillary tangles. Recent evidence suggests that soluble forms of both A? and tau can influence cognition and A? has been shown to modulate tau pathology. However, the A? species that mediates these effects remains largely unresolved. The Arctic A? mutation (E22G) has recently been shown to enhance soluble A? protofibril formation and cause early-onset familial AD, providing strong genetic evidence that A? aggregation state is critical to the development of AD. In this proposal, we will utilize the Arctic mutation to test the hypothesis that soluble A? assemblies induce tau pathology and cognitive dysfunction. To facilitate my investigation and greatly enhance my career development, I will receive mentorship from Dr. Frank LaFerla in the design, generation and analysis of transgenic AD models. In addition, Dr. James McGaugh and Dr. Charles Glabe will provide me with training in behavioral analyses and oligomeric protein biochemistry respectively.
In Aim 1, we will utilize the Arctic A? mutation to develop novel transgenic models of AD with age-dependent and progressive neuropathology to test the hypothesis that soluble A? assemblies promote tau pathology from wild type hTau. We anticipate that this model will develop A? and tau pathologies without the use of mutant tau, thereby more closely representing the etiology of AD.
In Aim 2, we will assess cognitive phenotype and correlations with A? and tau pathology. Soluble Arctic A? inhibits hippocampal LTP 100-fold more potently than wild-type A?. Therefore, we hypothesize that the Arctic mutation will rapidly produce cognitive dysfunction via enhancing the generation of soluble A? assemblies and modulating the development of tau pathology. Under the guidance of Dr. James McGaugh, I will test this hypothesis by performing a cross-sectional analysis of cognitive function in our novel transgenic models and determine whether cognitive deficits correlate with pathological progression.
In Aim 3 we will test the hypothesis that soluble A? assemblies induce tau pathology and mediate cognitive decline. In this aim, Dr. Charles Glabe will provide guidance on oligomeric protein biochemistry and his conformational-dependent antibodies will be utilized to test this hypothesis. Combined the proposed aims seek to determine whether soluble A? assemblies play a key role in the development of tau pathology and cognitive dysfunction.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
Project #
Application #
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Miller, Marilyn
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Other Basic Sciences
Schools of Arts and Sciences
United States
Zip Code
Blurton-Jones, Mathew; Spencer, Brian; Michael, Sara et al. (2014) Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. Stem Cell Res Ther 5:46
Poon, Wayne W; Blurton-Jones, Mathew; Tu, Christina H et al. (2011) ?-Amyloid impairs axonal BDNF retrograde trafficking. Neurobiol Aging 32:821-33
Freude, Kristine K; Penjwini, Mahmud; Davis, Joy L et al. (2011) Soluble amyloid precursor protein induces rapid neural differentiation of human embryonic stem cells. J Biol Chem 286:24264-74
Clinton, Lani K; Blurton-Jones, Mathew; Myczek, Kristoffer et al. (2010) Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci 30:7281-9
Koike, Maya A; Green, Kim N; Blurton-Jones, Mathew et al. (2010) Oligemic hypoperfusion differentially affects tau and amyloid-{beta}. Am J Pathol 177:300-10
Blurton-Jones, Mathew; Kitazawa, Masashi; Martinez-Coria, Hilda et al. (2009) Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A 106:13594-9