Role of iron and aluminum in brain metabolism

Author

Martin Clauberg

Date of Award

5-1992

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Biochemistry and Cellular and Molecular Biology

Major Professor

J. G. Joshi

Committee Members

Jorges E. Churchich, Walter R. Farkas, Daniel M. Roberts

Abstract

Several aspects of the involvement of iron and aluminum in the functioning of the brain were investigated.

Magnetic resonance imaging, and biochemical assays for both iron and ferritin were performed for different regions on normal and diseased brains. Iron concentrations varied significantly in neurologically intact brains, as well as those of Parkinson's and Huntington's diseased patients. Iron concentration of the putamen brain region was elevated approximately 300% and 33% over control values in Huntington's and Parkinson's disease, respectively. Values for ferritin determined by immunoradiometric assays were constant among different regions of control brains, but the putamen of Huntington's disease showed a 600% increase over that of the control region. However, contrary to a previously suggested hypothesis, we did not observe a correlation between the shortening of the T2 relaxation time constants and either iron or ferritin values in the normal and diseased brain.

The interactions of aluminum with in vitro proteolysis and with in vivo glucose metabolism in the brain were studied.

The existence of an aggregated polymer of the 42/43 amino acid long Β-amyloid peptide (Β-AP) in the cerebral plaques is perhaps the most consistent feature in Alzheimer's disease (AD). This peptide is believed to arise by proteolytic processing from Β-amyloid precursor proteins of varying length (Β-APP_{695,714,750,770}).In vitro, aluminum activates Α-chymotrypsin 200% at pH 6.5. Aluminum also renders Α-1-chymotrypsin highly resistant (over 100-fold increase in K_I) to inhibition by bovine pancreatic trypsin inhibitor, as well as a fusion protein containing the inhibitory domain of Β-APP, and, to a lesser degree, to Α-1-antichymotrypsin. We propose that in Alzheimer's disease, aluminum accelerates proteolytic processing of Β-APP and permits Β-AP formation despite the presence of the inhibitory domain of the Β-APP.

Male Sprague-Dawley rats were exposed to 100 μiM AlCl₃ in the drinking water for two years. The local in vivo cerebral metabolic rates for glucose (ICMR_glc) were determined with the [¹⁴C]-2-deoxyglucose method in 23 brain regions of six aluminum-treated rats and four age-matched controls. Aluminum treatment reduces the ICMR_glc in the ventral pallidum and temporal cortex by 14% at the 95% confidence level (Student's t-test and analysis of variance). Furthermore, the average glucose utilization of the brain as a whole was weighted for its component parts. The 6% reduction of average glucose utilization found in the aluminum-treated rats approaches statistical significance (p = 0.095). Other physiological determinants appeared to be affected, but not at a statistically significant level. Aluminum's involvements with several steps of glucose metabolism appear to be inhibitory.

Recommended Citation

Clauberg, Martin, "Role of iron and aluminum in brain metabolism. " PhD diss., University of Tennessee, 1992.
https://trace.tennessee.edu/utk_graddiss/10861