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 A40,42 species and consequently lowers Adeposits. 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.
Alzheimer's disease (AD) is a chronic, progressive dementia associated with impairment in memory and behavior. It currently accounts for about 70% of all dementias and onset typically occurs in mid-late life. The frequency doubles every five years after age 60, increasing from a prevalence of about 1% in individuals aged 60 years to about 40% among those aged 85 years or greater. Thus this disease is a clear healthcare problem for all individuals living past the age of 60. In terms of healthcare costs, it's estimated that the toal direct and indirect costs related to AD alone are, on a per-patient basis, some $91,000 over the course the illness. In this application, we will evaluate the therapeutic effectiveness of orally administered diosmin, a natural small-molecular weight compound, in reducing cognitive impairment in 3XTg-AD mice, a transgenic model of AD, and correlation of this effect with reducing cerebral -amyloid and tau pathology as well as microgliosis/neuroinflammation. These studies could lay the foundation for AD clinical trials with diosmin diet supplementation in the near future.
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