Abstract

Alzheimer's disease (AD) is defined neuropathologically by extracellular plaques composed of ?-amyloid (A?) and intracellular tangles consisting of hyperphosphorylated forms of the microtubule-associated protein tau. A? accumulation and hyperphosphorylation of tau are recognized as key events leading to full blown AD neuropathology. Here we propose to use a unique set of small molecule drugs (gamma-secretase modulators and CRFR1 antagonists) to further explore novel AD therapeutics. This application will focus on the efficacy of drugs aimed at both A?- and tau-related pathologies in AD transgenic mice. Our overarching hypothesis is combination therapy aimed to disrupt production of both A?42 and hyperphosphorylated tau will be an efficacious treatment approach for prodromal or early AD.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG047484-01A1
Application #
8771201
Study Section
Cell Death and Injury in Neurodegeneration Study Section (CDIN)
Program Officer
Refolo, Lorenzo
Project Start
2014-09-01
Project End
2016-04-30
Budget Start
2014-09-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093

  Publications

Kim, Changyoun; Spencer, Brian; Rockenstein, Edward et al. (2018) Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating ?-synuclein transmission and neuroinflammation. Mol Neurodegener 13:43
Zlatar, Zvinka Z; Bischoff-Grethe, Amanda; Hays, Chelsea C et al. (2016) Higher Brain Perfusion May Not Support Memory Functions in Cognitively Normal Carriers of the ApoE ?4 Allele Compared to Non-Carriers. Front Aging Neurosci 8:151
Le, Michelle H; Weissmiller, April M; Monte, Louise et al. (2016) Functional Impact of Corticotropin-Releasing Factor Exposure on Tau Phosphorylation and Axon Transport. PLoS One 11:e0147250
Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H et al. (2016) Corticotropin-releasing factor receptor-1 antagonism mitigates beta amyloid pathology and cognitive and synaptic deficits in a mouse model of Alzheimer's disease. Alzheimers Dement 12:527-37
Winston, Charisse N; Goetzl, Edward J; Akers, Johnny C et al. (2016) Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile. Alzheimers Dement (Amst) 3:63-72
Zhang, Cheng; Kuo, Ching-Chang; Moghadam, Setareh H et al. (2015) Corticotropin-Releasing Factor Receptor-1 Antagonism Reduces Oxidative Damage in an Alzheimer’s Disease Transgenic Mouse Model. J Alzheimers Dis 45:639-50
Campbell, Shannon N; Zhang, Cheng; Roe, Allyson D et al. (2015) Impact of CRFR1 Ablation on Amyloid-? Production and Accumulation in a Mouse Model of Alzheimer's Disease. J Alzheimers Dis 45:1175-84
Rafii, Michael S; Wishnek, Hannah; Brewer, James B et al. (2015) The down syndrome biomarker initiative (DSBI) pilot: proof of concept for deep phenotyping of Alzheimer's disease biomarkers in down syndrome. Front Behav Neurosci 9:239
Steinmetz, Danielle; Ramos, Eugenia; Campbell, Shannon N et al. (2015) Reproductive Stage and Modulation of Stress-Induced Tau Phosphorylation in Female Rats. J Neuroendocrinol 27:827-34
Wagner, Steven L; Zhang, Can; Cheng, Soan et al. (2014) Soluble ?-secretase modulators selectively inhibit the production of the 42-amino acid amyloid ? peptide variant and augment the production of multiple carboxy-truncated amyloid ? species. Biochemistry 53:702-13

Showing the most recent 10 out of 11 publications