Project 2: Novel NeurosERMs and NeurosARMs for Protection Against Alzheimer Pathology Roberta Diaz Brinton, PhD, PI and Christian J. Pike, PhD, PI Our goal is to develop safe and efficacious alternative hormone therapies to prevent or delay late-onset age-associated Alzheimer's disease (AD). This proposal builds on our extensive knowledge of the mechanisms of estrogen and androgen action in brain and the extensive epidemiological data indicating that estrogen-based hormone therapy reduces the risk of developing AD and the emerging findings that androgen therapy can sustain cognitive function during aging. Basic science analyses of gonadal hormone action in neurons provide a mechanistic understanding for the healthy cell bias of hormone action. Studies proposed herein are a preclinical plan to translate our basic understanding of gonadal hormone mechanisms in brain into rationally designed molecules that will function as brain selective estrogen receptor modulators (NeurosERMs) and androgen receptor modulators (NeurosARMs). The proposed translational analyses build on several decades of basic science discovery that have established the solid foundation of predictive gonadal hormone outcomes in brain. It is on this foundation that we propose to develop innovative, safe and efficacious alternatives to hormone therapy to sustain neurological health and to prevent the dysfunction and pathology of late-onset age-associated AD.
Specific Aim I proposes in vitro screens of NeurosERM and NeurosARM candidate molecules for efficacy to induce markers of neuroprotection, neural defense, neural plasticity. Further, we will assess the ability of candidate NeurosERMs and NeurosARMs to reduce B-amyloid accumulation and tau hyperphosphorylation. Consistent with the mission of the USC ADRC, we will also evaluate indicators of vascular viability and integrity to access efficacy of NeurosERMs / sARMs to prevent vascular disease. Molecules that reach criterion for in vitro efficacy will move to in vivo testing in Aim II.
In Specific Aim II, we will evaluate efficacies of NeurosERM and NeurosARM candidate molecules in a transgenic mouse model of AD to 1) reduce levels of tau phosphorylation and B-amyloid accumulation;2) prevent cognitive deficits;3) protect against vascular injury;and 4) prevent proliferation in reproductive tissues.

Public Health Relevance

Abundant research at multiple levels indicates that estrogen- and androgen-based therapies in aging women and men, respectively, have therapeutic efficacy in reducing risk of Alzheimer and vascular diseases. This project will identify novel mimetics of estrogen (NeurosERMs) and androgens (NeurosARMs) for translational purposes that will protect the brain and vasculature but lack deleterious effects of reproductive tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005142-29
Application #
8450815
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
29
Fiscal Year
2013
Total Cost
$199,475
Indirect Cost
$78,234
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Soosman, Steffan K; Joseph-Mathurin, Nelly; Braskie, Meredith N et al. (2016) Widespread white matter and conduction defects in PSEN1-related spastic paraparesis. Neurobiol Aging 47:201-209
Kammen, Alexandra; Law, Meng; Tjan, Bosco S et al. (2016) Automated retinofugal visual pathway reconstruction with multi-shell HARDI and FOD-based analysis. Neuroimage 125:767-79
Forrester, Sarah N; Gallo, Joseph J; Smith, Gwenn S et al. (2016) Patterns of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Risk of Dementia. Am J Geriatr Psychiatry 24:117-25
Barnes, Samuel R; Ng, Thomas S C; Montagne, Axel et al. (2016) Optimal acquisition and modeling parameters for accurate assessment of low Ktrans blood-brain barrier permeability using dynamic contrast-enhanced MRI. Magn Reson Med 75:1967-77
Kennedy, Richard E; Cutter, Gary R; Wang, Guoqiao et al. (2016) Post Hoc Analyses of ApoE Genotype-Defined Subgroups in Clinical Trials. J Alzheimers Dis 50:1205-15
Ebbert, Mark T W; Boehme, Kevin L; Wadsworth, Mark E et al. (2016) Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk. Alzheimers Dement 12:121-9
Finch, Caleb E; Shams, Sara (2016) Apolipoprotein E and Sex Bias in Cerebrovascular Aging of Men and Mice. Trends Neurosci 39:625-37
Crawford, Karen L; Neu, Scott C; Toga, Arthur W (2016) The Image and Data Archive at the Laboratory of Neuro Imaging. Neuroimage 124:1080-3
Bilousova, Tina; Miller, Carol A; Poon, Wayne W et al. (2016) Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases. Am J Pathol 186:185-98
Halliday, Matthew R; Rege, Sanket V; Ma, Qingyi et al. (2016) Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease. J Cereb Blood Flow Metab 36:216-27

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