The present application is in response to PAR-03-056, with particular focus on the topic of Functional Senescence. Age is the strongest risk factor for Alzheimer's disease (AD), the most common cause of dementia in the U.S. Evidence suggests brain accumulation of soluble amyloid-beta (A-beta) peptide into insoluble amyloid is central to the pathogenesis of AD. While overproduction of A-beta leads to its premature accumulation in rare familial AD, there is no evidence of overproduction in sporadic AD (>99% of AD cases). Thus, why does A-beta accumulate in an age-dependent manner in the most common form of AD? Although much is known about production of A-beta, very little is known about its metabolism. A-beta accumulation may be a result of impaired A-beta clearance from the brain to the blood. Molecules exit the brain through the blood-brain barrier (BBB) or via bulk flow through interstitial fluid or cerebrospinal fluid drainage pathways. Reports have demonstrated efflux of A-beta peptides out of the CNS, and studies suggest a possible role for MDR1 P-glycoprotein (Pgp), a transporter expressed by cells of the BBB, in this process. If Pgp plays a role as an A-beta efflux pump, it may also influence A-beta deposition and AD, as suggested by a recent descriptive study. We hypothesize that there is a defect in the normal clearance mechanism(s) of A-beta from the CNS to the blood with age, and that this impairment ultimately contributes to A-beta accumulation in the brain and its deposition as insoluble amyloid. We propose to characterize Abeta efflux in mice as a function of age and investigate the role of Pgp in this process, and in A-beta deposition in a mouse model of AD. A-beta and control molecules with known transport mechanisms will be injected into the brains of mice of different ages and efflux kinetics will be assessed in wild type and mdrla/b -/- mice and in wild type mice treated with Pgp inhibitors. We will also assess brain A-beta deposition and Abeta levels in APPsw (Tg2576) transgenic mice that have been bred with mdrla,b -/- mice lacking Pgp. Support for the hypothesis would establish a role for age-dependent defects in A-beta clearance from the brain in the pathogenesis of AD and, importantly, provide a novel therapeutic target for treatment of the disease.
| Cirrito, John R; Deane, Rashid; Fagan, Anne M et al. (2005) P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest 115:3285-90 |
