There may be a dual role of ?-secretase in AD. The cleavage of APP by ?-secretase is key in the pathogenesis of AD and amyloid accumulation in the brain. As such, ?-secretase has been targeted for years for development of AD therapies and ?-secretase inhibitors (GSIs). Most recently it was shown that a mutation in presenilin affecting ?-secretase activity may impair microglial phagocytosis of A? and promote amyloid accumulation. Because GSIs may impair salutary microglia activity via inhibition of Notch signaling pathway, we seek to develop a new class of flavonoids GSIs that can reduce ?-APP cleavage yet minimize their potential negative effect on microglia phagocytosis activity. Optimally we would seek to do the former while promoting the latter. Turning to diosmin's efficacy as promoting both anti-amyloidogenic APP processing and microglial phagcytosis of A?? we have recently shown that the treatment of Tg2576 mice with diosmin markedly reduces cerebral A?40,42 species and consequently lowers A? deposits. Based on this finding, its diosmetin metabolite becomes our focus on preliminary studies. These results indicate that diosmin/diosmetin not only reduces A? by inhibiting ?-APP cleavage but also decreases hyperphosphorylated tau by modulating GSK-3? activation and enhances microglial anti-inflammatory and phagocytotic phenotype switching. These new results fully support our present hypothesis that diosmin could have a therapeutic effect in AD by reducing cognitive impairment while also reducing cerebral ?-amyloid levels, tau pathology and microglial/neuroinflammation. In this application, the flavonoid-diosmin will be orally administered to 3XTg-AD mice before (prophylactic treatment group) or after (therapeutic treatment group) development of AD-like pathology. Groups of untreated non-transgenic littermates will be compared to the transgenic treatment groups. Oral administration of diosmin to these mice will begin at 4 and 6 months of age and continued for 6 months.
For Aim 1, cognitive testing will be done at several ages following the administration.
For Aim 2, we will sacrifice these mice at several ages to examine histological and biochemical endpoints related to amyloid deposition and tau hyperphosphorylation and correlate pathological changes with cognitive performance.
For Aim 3, we will test the hypothesis that diosmin treatment preserves the anti-inflammatory and phagocytic phenotype in primary microglia from young and aged 3XTg-AD mice. These studies could lay the foundation for AD clinical trials with diosmin diet supplementation in the near future.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
1R01AT007411-01A1
Application #
8627446
Study Section
Special Emphasis Panel (ZAT1)
Program Officer
Williamson, John S
Project Start
2014-09-01
Project End
2016-06-30
Budget Start
2014-09-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of South Florida
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
Hou, Huayan; Habib, Ahsan; Zi, Dan et al. (2017) Low-Density Lipoprotein Receptor-Related Protein-1 (LRP1) C4408R Mutant Promotes Amyloid Precursor Protein (APP) ?-Cleavage in Vitro. Neuromolecular Med 19:300-308
Habib, Ahsan; Sawmiller, Darrell; Tan, Jun (2017) Restoring Soluble Amyloid Precursor Protein ? Functions as a Potential Treatment for Alzheimer's Disease. J Neurosci Res 95:973-991
Habib, Ahsan; Sawmiller, Darrell; Li, Song et al. (2017) LISPRO mitigates ?-amyloid and associated pathologies in Alzheimer's mice. Cell Death Dis 8:e2880
Sawmiller, Darrell; Li, Song; Mori, Takashi et al. (2017) Beneficial effects of a pyrroloquinolinequinone-containing dietary formulation on motor deficiency, cognitive decline and mitochondrial dysfunction in a mouse model of Alzheimer's disease. Heliyon 3:e00279
PĂ©rez, Christine; Sawmiller, Darrell; Tan, Jun (2016) The role of heparan sulfate deficiency in autistic phenotype: potential involvement of Slit/Robo/srGAPs-mediated dendritic spine formation. Neural Dev 11:11
Sawmiller, Darrell; Habib, Ahsan; Li, Song et al. (2016) Diosmin reduces cerebral A? levels, tau hyperphosphorylation, neuroinflammation, and cognitive impairment in the 3xTg-AD mice. J Neuroimmunol 299:98-106
Deng, Juan; Habib, Ahsan; Obregon, Demian F et al. (2015) Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3? signaling pathway. J Neurochem 135:630-7
Li, Song; Hou, Huayan; Mori, Takashi et al. (2015) Swedish mutant APP-based BACE1 binding site peptide reduces APP ?-cleavage and cerebral A? levels in Alzheimer's mice. Sci Rep 5:11322
Habib, Ahsan; Deng, Juan; Hou, Huayan et al. (2013) Mycoplasma hyorhinis markedly degrades ?-amyloid peptides in vitro and ex vivo: a novel biological approach for treating Alzheimer's disease? Am J Transl Res 5:634-42
Smith, Adam J; Kim, Seol-Hee; Duggirala, Naga K et al. (2013) Improving lithium therapeutics by crystal engineering of novel ionic cocrystals. Mol Pharm 10:4728-38

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