Alzheimer Disease: Beard J

House MJ, St Pierre TG, Kowdley KV, Montine T, Connor J, Beard J, Berger J, Siddaiah N, Shankland E, Jin LW. · School of Physics, University of Western Australia, Perth, Australia. · Magn Reson Med. · Pubmed #17191232 No free full text.

Abstract: Iron accumulates in the Alzheimer's disease (AD) brain and is directly associated with beta-amyloid pathology. The proton transverse relaxation rate (R(2)) has a strong linear relationship with iron concentrations in healthy brain tissue; however, an independent test of this relationship has not been extended to AD brain tissue. In this study in vitro single spin-echo (SE) measurements were made on tissue samples from four human AD brains using a 4.7T MRI research scanner. R(2) values were calculated for 14 cortical and subcortical gray matter (GM) and white matter (WM) regions. Atomic absorption spectroscopy was used to measure iron concentrations in the corresponding excised brain regions. Significant positive linear correlations were observed between R(2) values and iron concentrations in GM regions assessed across individual tissue samples and data averaged by brain region. With the use of a predictive model for R(2), a threshold iron concentration of 55 microg Fe/g wet tissue was determined above which R(2) appears to be dominated by the affects of iron in AD brain tissue. High-field MRI may therefore be a useful research tool for assessing brain iron changes associated with AD.

Kukar T, Murphy MP, Eriksen JL, Sagi SA, Weggen S, Smith TE, Ladd T, Khan MA, Kache R, Beard J, Dodson M, Merit S, Ozols VV, Anastasiadis PZ, Das P, Fauq A, Koo EH, Golde TE. · Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA. · Nat Med. · Pubmed #15834426 No free full text.

Abstract: Increased Abeta42 production has been linked to the development of Alzheimer disease. We now identify a number of compounds that raise Abeta42. Among the more potent Abeta42-raising agents identified are fenofibrate, an antilipidemic agent, and celecoxib, a COX-2-selective NSAID. Many COX-2-selective NSAIDs tested raised Abeta42, including multiple COX-2-selective derivatives of two Abeta42-lowering NSAIDs. Compounds devoid of COX activity and the endogenous isoprenoids FPP and GGPP also raised Abeta42. These compounds seem to target the gamma-secretase complex, increasing gamma-secretase-catalyzed production of Abeta42 in vitro. Short-term in vivo studies show that two Abeta42-raising compounds increase Abeta42 levels in the brains of mice. The elevations in Abeta42 by these compounds are comparable to the increases in Abeta42 induced by Alzheimer disease-causing mutations in the genes encoding amyloid beta protein precursor and presenilins, raising the possibility that exogenous compounds or naturally occurring isoprenoids might increase Abeta42 production in humans.

Thompson K, Menzies S, Muckenthaler M, Torti FM, Wood T, Torti SV, Hentze MW, Beard J, Connor J. · Department of Neuroscience and Anatomy, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA. · J Neurosci Res. · Pubmed #12478613 No free full text.

Abstract: Several neurodegenerative disorders such as Parkinson's Disease (PD) and Alzheimer's Disease (AD) are associated with elevated brain iron accumulation relative to the amount of ferritin, the intracellular iron storage protein. The accumulation of more iron than can be adequately stored in ferritin creates an environment of oxidative stress. We developed a heavy chain (H) ferritin null mutant in an attempt to mimic the iron milieu of the brain in AD and PD. Animals homozygous for the mutation die in utero but the heterozygotes (+/-) are viable. We examined heterozygous and wild-type (wt) mice between 6 and 8 months of age. Macroscopically, the brains of +/- mice were well formed and did not differ from control brains. There was no evidence of histopathology in the brains of the heterozygous mice. Iron levels in the brain of the +/- and wild-type (+/+) mice were similar, but +/- mice had less than half the levels of H-ferritin. The other iron management proteins transferrin, transferrin receptor, light chain ferritin, Divalent Metal Transporter 1, ceruloplasmin, were increased in the +/- mice compared to +/+ mice. The relative amounts of these proteins in relation to the iron concentration are similar to that found in AD and PD. Thus, we hypothesized that the brains of the heterozygote mice should have an increase in indices of oxidative stress. In support of this hypothesis, there was a decrease in total superoxide dismutase (SOD) activity in the heterozygotes coupled with an increase in oxidatively modified proteins. In addition, apoptotic markers Bax and caspase-3 were detected in neurons of the +/- mice but not in the wt. Thus, we have developed a mouse model that mimics the protein profile for iron management seen in AD and PD that also shows evidence of oxidative stress. These results suggest that this mouse may be a model to determine the role of iron mismanagement in neurodegenerative disorders and for testing antioxidant therapeutic strategies.