Others have confirmed this finding. Our laboratory then studied the Iar emphasis is placed on transport, magnetism, superconductivity,

effects of AB on brain membrane systems to see if this peptide would device fabrication and miniaturization, and the discovery of new

lead to cell death. Using a variety of biophysical and bioanalytical classes of electronic materials. We are currently working on the syn-

methods, we demonstrated that, in ways completely inhibited by free thesis and solid state properties of neutral carbon-based radicals,

radical antioxidants, AB induced: (a) brain membrane lipid carbon nanotubes and organic light-emitting diodes. Our work on

peroxidation; (b) brain cell protein oxidation; (0) ROS formation; and carbon nanotubes [CNTs] was recently reported in Science, (282

(d) neuronal cell death. A major lipid peroxidation product is 4-hy— (1998) 95) and highlighted in Chemical and Engineering News (Oc-

droxy-2-trans-nonenal (HNE). This compound adds to cysteine SH tober 5, 1998).

groups and other amino acids by Michael addition. AB added to neu- All previous work on CNTs (both single—walled and multi-walled),

rons leads to formation of HNE, and, at these concentrations, HNE has been carried out on the unusual intractable, insoluble form of this

caused large changes in brain membrane protein conformation. material. This form of the material is not amenable to many of the
. These changes likely account for alterations in neuronal transport processing steps thatare necessary if the CNTs are to reach theirfull

function by AB and HNE. Since HNE was found to be in excess in AD potential -- particularly in applications that require these materials in

brain, it is possible that this agent accounts for altered function of the form of polymers, copolymers, composites, ceramics and mold-
! many proteins in this disorder. able forms. While some of the present forms of the CNTs can be
‘ Research in our group also showed that neuronal protein oxida- heterogeneously dispersed in various media, the interactions between

tion induced by AB was inhibited by the free radical scavenger vita- the CNTs and host and between the CNTs themselves are simply

min E and that vitamin E also blocked AB—induced lipid peroxidation, physical, and Without the formation of chemical bonds the advanta-

ROS formation, and inhibition of Nat/Kt-ATPase. The latter study geous properties of the CNTs are unlikely to be realized on a macro-

was performed collaboratively with Dr. Mark Mattson of the UK Cen— scopic level. What is needed is a method to prepare well-dispersed

ter on Aging. Inhibition of this enzyme would lead to opening of volt- forms of CNTs by inducing them to dissolve in organic solvents. Al-

age-controlled Ca2+ channels, and since there is a 10,000-fold con- though long believed to be impossible, we have discovered such a

centration gradient of this ion, excess Caz+ would accumulate inside procedure for the dissolution of SWNTs. Naked single-walled

the neuron. Indeed, Dr. Mattson's and our groups have found that nanotube carbon metals and semiconductors were dissolved in or-

AB leads to excess Ca2+ accumulation, leading to subsequent detri- ganic solutions (s-SWNTs) by chemical processing of the nanotube

mental processes that eventually kill the neuron, exactly in accor- end groups. Both ionic (charge transfer) and covalent solution phase

dance with our hypothesis for neurotoxicity in AD brain. chemistry with concomitant modulation of the SWNT electronic band

A different oxidative stress pathway, but related to AB, involves structure were demonstrated. Solution phase near—IR spectroscopy

peroxynitrite. This anion is formed by rapid reaction of superoxide was used to study the effects of chemical modifications on the band

radical anion with nitric oxide. The latter is produced with catalytic transitions of the SWNTs. Reaction of s-SWNTs with dichlorocarbene

assistance of nitric oxide synthetase, which is stimulated by AB. Su- led to functionalization of the nanotube walls.

peroxide radical, though formed in many reactions, is principally pro-

duced in mitochondria and leaks from this organelle. Peroxynitrite Chemical Attachment of Organic Functional Groups to Single-

rapidly reacts with tyrosine residues to form 3-nitrotyrosine, which, Walled Carbon Nanotubes

because of its proximity to the OH group on tyrosine, prevents phos-

phorylation of the latter, thereby blocking a key step in cell signaling, . _ h .. - H

a detriment to the cell. This anion may also lead to free radicals y’é,f C" \ .

through breakdown to NO2 and OH radicals. Our group recently ”’ “R‘R‘ ‘

showed that peroxynitrite greatly alters the conformation of brain ’ " Kafka \ , \

membrane proteins, leads to significantly increased protein oxidation \ QQ‘

and neuronal cell death. The endogenous free radical scavenger, ... s" a? i ’ \ ’

glutathione, blocks these alterations. These results are particularly ‘ a, ,. ,ty’” \

exciting in that they have implications of therapy in AD. 33".

Mechanistic studies are ongoing in our lab to try and better un- ' /ya / , \ /

derstand AB—associated free radical oxidative stress. It is possible “. 1' 7’1" '

that redox metals play a role in this phenomenon. Harvard research— ' “‘ ty”

ers have shown recently that AB will reduce Cu2+ to Cu+, i.e., like our ' “‘~’{f 13).?

findings, the peptide transfers an electron to the metal ion leaving a ' ‘—-'” '5 " -’—

free radical on the peptide. Our studies point to a role for methionine

in the oxidative stress properties of AB and that if methionine is re-

placed by different amino acids or removed all together, no EPR sig- Subatomic Chemistry

nals, no protein oxidation, and no neurotoxicity results. These in-

vitro studies were recently supported by in-vivo studies in our labora- Steven W. Yates. I usually describe my work at UK as basic nuclear

. tory. In collaboration with a scientist at the University of Colorado, structure research, but Bob Guthrie has suggested that we need a
who provided transgenic worms, C. elegans, in Which human AB was more alluring image and that what I actually do is "subatomic chem-
expressed, we showed a nearly 100% increase in protein carbonyl istry.“ I kind of like that description and think I'll use it, at least until
levels over the vector control. If methionine were mutated to a differ- Bob comes up with something even better.

't ent amino acid the AB expressed in the transgenic worm, no increased The basic goal of our work, understanding the fundamental prop-
protein carbonyls were found, consistent with a role for methionine erties of atomic nuclei, has remained unchanged since I arrived at
found in the in-vitro studies noted above. These in-vivo studies also UK in the Summer of 1975. The most exciting developments in this
are consistent with our earlier studies showing increased protein car— area are in the unfolding of our knowledge of various so-called col-
bonyls in AD brain. lective modes in nuclei. These excitations represent correlated mo—

tions of a large number of nucleons, neutrons or protons, in the

Carbon Nanotubes nucleus. The simplest collective excitations can be visualized by anal-

ogy with the motion of a soap bubble, which can vibrate and rotate

Robert C. Haddon. Our group is interested in the synthesis, elec— around an axis; these are called vibrational and rotational modes and

tronic structure and properties of molecules and materials. Particu- have direct analogs inmolecules. Rotations can only occurin a quantal
7