As our nation ages, the neurological diseases of later adulthood have become more prevalent. The number of Alzheimer's disease (AD) diagnoses has increased in the past decades, taking a large financial and emotional toll on our health care system. What makes some patients more susceptible to AD than others? Over twenty years ago, the ApoE4 allele was identified as a major genetic risk factor for late onset AD (1, 2). One of ApoE4's effects in the central nervous system (CNS) is to reduce the ability of neurons to respond to reelin signaling (3). Reelin is a neuromodulator that decreases with age and is especially reduced in Alzheimer's disease (4, 5). In vitro, reelin promotes synaptic plasticity, an mice injected with reelin intra- ventricularly have improved performance on learning and memory tasks (6, 7). Importantly, reelin protects in vitro against the toxicity induced by A oligomers, a toxic particle that builds up gradually in Alzheimer's disease (8-10). Additionally, a recent study demonstrated that Reelin overexpression in a mouse model of AD rescued cognitive defects and delayed amyloid plaque development (11). Genetic studies on the effect of reelin loss in mice have been hindered by the fact that reelin plays a large role in brain development (12). To circumvent the problem presented by this developmental issue, we have generated a conditional reelin knockout mouse in which reelin is expressed normally until the mice are injected with Tamoxifen. I will use this mouse to study the effect of reelin loss in aging related disease phenotypes. To determine the clinical relevance of reelin reduction in AD, it is important to study these conditional reelin knockout mice on a background of normal adult synaptic plasticity as well as Alzheimer's disease pathology. Initial results from my preliminary data and the literature suggest that reelin has a protective effect against A-induced neurodegeneration. The primary goals of this research are to 1) elucidate the role reelin has in normal adult synaptic function; 2) determine the role in vivo for reelin to combat A toxicity. These goals will be accomplished by a combination of behavioral studies of learning and memory, electrophysiological experiments on synaptic function, and biochemical and histological characterization. To study the protective role of reelin against AD, I will cross the conditional knockout mice with APPSwe mice, an Alzheimer's disease mouse model that expresses high levels of A.The data generated by this study can be used to propose new models of the role of reelin in adult neuronal function and AD and generate new therapeutic ideas to use alterations in reelin levels as a neuroprotective agent in neurological diseases of aging.

Public Health Relevance

As our population ages, the portion of Americans affected by Alzheimer's disease (AD) has skyrocketed. ApoE4 is the main genetic risk factor for AD, and understanding the underlying molecular mechanisms by which ApoE4 contributes to disease onset and prognosis is a key to developing targeted therapies for AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30AG047799-02
Application #
8955628
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2014-09-15
Project End
2016-05-14
Budget Start
2015-09-15
Budget End
2016-05-14
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Lane-Donovan, Courtney; Herz, Joachim (2017) The ApoE receptors Vldlr and Apoer2 in central nervous system function and disease. J Lipid Res 58:1036-1043
Kounnas, Maria Z; Lane-Donovan, Courtney; Nowakowski, Dan W et al. (2017) NGP 555, a ?-Secretase Modulator, Lowers the Amyloid Biomarker, A?42, in Cerebrospinal Fluid while Preventing Alzheimer's Disease Cognitive Decline in Rodents. Alzheimers Dement (N Y) 3:65-73
Lane-Donovan, Courtney; Herz, Joachim (2017) ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease. Trends Endocrinol Metab 28:273-284
Lane-Donovan, Courtney; Herz, Joachim (2016) High-Fat Diet Changes Hippocampal Apolipoprotein E (ApoE) in a Genotype- and Carbohydrate-Dependent Manner in Mice. PLoS One 11:e0148099
Lane-Donovan, Courtney; Wong, Wen Mai; Durakoglugil, Murat S et al. (2016) Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice. J Neurosci 36:10141-50
Lane-Donovan, Courtney; Desai, Charisma; Pohlkamp, Theresa et al. (2016) Physiologic Reelin does not play a strong role in protection against acute stroke. J Cereb Blood Flow Metab 36:1295-303
Lane-Donovan, Courtney; Philips, Gary T; Wasser, Catherine R et al. (2015) Reelin protects against amyloid ? toxicity in vivo. Sci Signal 8:ra67
Pohlkamp, Theresa; Durakoglugil, Murat; Lane-Donovan, Courtney et al. (2015) Lrp4 domains differentially regulate limb/brain development and synaptic plasticity. PLoS One 10:e0116701
Lane-Donovan, Courtney; Herz, Joachim (2014) Is apolipoprotein e required for cognitive function in humans?: implications for Alzheimer drug development. JAMA Neurol 71:1213-5