xt73n58ck19b https://exploreuk.uky.edu/dips/xt73n58ck19b/data/mets.xml University of Kentucky. Office of the Vice President for Research and Graduate Studies Kentucky University of Kentucky. Office of the Vice President for Research and Graduate Studies 2004 volumes. Call Number: LD2762.9 .K38c. Accession Number: 2018ua049 journals LD2762.9 .K38c English Office of the Vice President for Research and Graduate Studies  Contact the Special Collections Research Center for information regarding rights and use of this collection University of Kentucky Odyssey Magazine Research -- Kentucky -- Periodicals Education -- Research -- Periodicals Research -- Kentucky Odyssey: The Magazine of University of Kentucky Research and Graduate Studies, Spring 2004 text images Odyssey: The Magazine of University of Kentucky Research and Graduate Studies, Spring 2004 2004 2004 2026 true xt73n58ck19b section xt73n58ck19b The Fight against
Alzheimer’s Intensifies

 

  

Lee T. Todd in, President
Wendy Baldwin, Executive Vice President for Research

Delwood C. Collins. Senior Associate Vice President
for Research and infrastructure

Joseph L Fink ill. Vice President for Research
and Economic Development

Agriculture
M. Scott Smith, Dean

Arts and Sciences
Steven Hoch. Dean

Business and Economics
Devanathan Sudharshan. Dean

Communications

and information Studies Q

iDaiidJohnsonrDean UanEI'SltY Of Kentucky Research
Demlstw -

Sharon P iiirner, Dean S p f I n g 2 0 0 4
Design

David Mohnei; Dean

Education

James Cibuika. Dean

Engineering

ihomas \-\1 Lester Dean

Fine Arts
Robert Shai. Dean

Heaith Sciences
Thomas C, Robinson. {man

Law

«‘rlian Vi; Vestal, Dean cove r Sto [y

Medicine
Why Do Our Brains Betray Us?

lav A Perman. Dean

Nursing

“11‘0"“ i “timi- ”‘36“ For over 30 years, UK researchers have been using

mm science to battle Alzheimer’s. And the fight has
intensified. Current projects explore vitamin E and
selenium, incipient Alzheimer’s, enzymes A—beta

kenneth B. Roberts: Dean
SociatWork
and proteasome, DNA microarray technology, and

MY Hott’rnan Dean

 

Odyssey . . . .

0mg, memantine—the first FDA~approved medication to
”Miami treat Alzheimer’s. 2
Editor

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Associate Editor and Web Designer fe at u re S

Alicia P, Oregon
In Search of East Africa’s Ancestral Statues

Designer

Shear & Shear . . . .
Photomphe‘ Cultural anthropologist Monica Udvardy is teaming up
tee r> mamas Photography with U5. museums to stop global traffic in vigango
Printer (memorial statues) and return them to their creators,

we” “953 the Grrrama people of Kenya. 18
Odissci is oubtisheo {nice a war bV the
Office of the Execuiiie Vice President to;
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admin as, innoxatiie srhoiarship. and
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research enterprise.

Mark Summers and the Serious Business
of Political Cartoons

UK’s first Thomas D. Clark Endowed Professor of History dis-

 

‘r‘o recent; iree sufscgption, cusses the power of political cartoons and his nearlv
(Mat 1 ‘sw’ciu \ e U or . . . . 4
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Skin Patch Promised Land

Drug-delivery expert Audra Stinchcomb is developing a
first-of-its—kind prescription patch, a safe and legal method
to deliver marijuana-like chemicals to ease nausea and
stimulate appetite in people with AIDS and cancer. 33

2003-2004 University Research Professors

Carol Baskin: Seed Germination in the Tropics
Jeremy Popkin: Taking a New Turn into Autobiography 38

Research Outreach

Building a Stronger Safety Net for Children

Protecting at-risk kids is the goal of a UK-led.
10state project to train supervisors how to best
support social workers. 35

In Brief

Clues to Organ Regeneration

Good Cholesterol, Estrogen & Heart Disease
CAER’s Jim Hower Wins Thiessen Medal
Working toward a Healthier Environment
Rockefeller Humanities Fellows at UK

A Case of the “Baghdad Boil" 40

Book End
The Shifting Geopolitical World

Geography professor Stan Brunn is editor
of a collection of essays exploring the global
impact of 9/11. 44

 Why D , »
Our

Braln~

B et ray

Us?

The Fight against
Alzheimer’s
Intensifies

"'“u
( )

Frederick Schmitt,

a professor in UK's
Department of Neurol—
ogy and Sanders-Brown
Center on Aging, headed
up the university's part
of a recent clinical study
of memantine, an FDA~
approved drug that
slows deterioration

in cognition and the
ability to perform daily
acthities for patients with

dementia.

rederick Schmitt, a professor of neurol-

ogy at the University of Kentucky, has

two framed photographs on his office
walls in UK’s Sanders-Brown Center on Aging.
One is an MC. Escher print in which water
seems to run uphill, playing tricks on percep-
tion; stairways defy spatial sense and lead
back only to themselves. Directly across from
this, 1 see the famous Salvadore Dali self-por-
trait. Dali’s face is a skewed and melting clock,
his moustache the two clock-hands.

Both of these surrealistic pieces must ap-
proximate what it feels like to be in the grip of
Alzheimer’s disease. The world is suddenly
not what it’s always been. Time warps. Every—
day objects are otherworldly and disconcert—
ing.

My father, late in second-stage Alzheimer's,
would pick up a paperweight given to him for
his many years as president of the Wichita
Stamp Club and turn it over and over, trying to
figure out what it was and what it was doing
there on his nightstand. In the small house he
shared with my mother, he began to regularly
see his mother, dead 30 years, drifting through
the hallways at night.

By now, almost everyone reading these words
haslostagrandfather, agrandmother, a father,
amother,asiblingprfriendtotheall-demand-
ing claims of Alzheimer’s.

As the baby boomers have aged, the number
of people in this country with Alzheimer‘s
disease and related disorders has grown. Newly
published research suggests that 4.5 million
Americans now have Alzheimer’s and that the
numbers will swell to as many as 16 million by
mid—century unless a cure is found.

Here are a couple of other facts about
Alzheimer's. The disease now strikes more

 

 William Markesberv, with help from Ann Tudor in the Sanders—Brown
Center on Aging, examines brain tissue from a patient with probable
Alzheimer’s disease, :vtarkesbenx has been researching the causes of

dementia for over 30 years at LKV

than one in 30 Americans, slowiy causing memory toss,
CGttfttSiOIt, and. ultimately. death. Incidence increases
with age—about hatt the population that lives past 85
gets Aizheitner’s. And the disease is the third most costiv
in the United States, each year draining $100 billion
from the US. economy

How and why do we get Alzheimer’s disease? Why do
our brains betray us?

For over 30 years the University of Kentucky Sanders-
Brown Center on Aging has been working to under—
stand the mechanisms of Alzheimer’s. always with an
eye toward prevention. Dozens ot protects carried out
throagh the Alzheimer‘s Sisease Research Center have
made important inroads to otir understanding oi the
disease—who gets Alzheimer‘s and why—and research
in 2004 continues at a vigorous pace.

The protects discussed in the following pages are all
concerned with a common goal: prevention and—in
the ionger rim with the pooied knowledge of research—
ers worldwide—c u re of this devastating and dehuman-
izing disease,

Can a Combination of
Vitamin E and Selenium
Prevent Alzheimer's?
\N'iliiam Markesl’rery. the University of
Kentucky’spatriarchofAlzheimer‘sdis-
ease research anti director of the [K
Alzheimer’s Disease Research Center
tADRC). believesthe 1(9intAiZilt’iint‘Y‘S
disease is prevention He also believes
that vitatnin E is an important part of
this key. And though he is an uncom—
rnoniysoitspoken man he wants his E—
message to get out loud and clear

“So far. vitamin E has emerged as one
of the weapons we have against dee
tiientia.“ Markeshery says from his of—
lice in the Sanders—Brown Center on
Aging. where he has served as director
since limit “There are several other
things you can do to lower your risk of
gettingAlzheimer‘s.hutvitaminEtaken
in conjunction with vitamin C is impor—
tant—a previous study showed that vi-
tamin E is one factor that slows. siightly.
the progression of the disease. The im-
pt irtant thing tor individuals at risk is to
take vitamin Eand vitamin C airing with
ioiic acid prior to getting the disease.“

So what are these risk factors?

A major lactor is age: The risk of
developing Alzheimer's increases with
age, One out of every 10 persons ($5
years and older isavictim ofAlzheimei’s
disease. although some victims may he
in their this and Sits, Approximately 30

   
 
 
   
 
 
 
 
 
 
 
 
 
  
   
  
    
  
   
   
   
  
  
  
  
   
 
   

ALI A

  

percentofAmericansbetweenthe ages
of75 and 84,and almosthalfofthose 85
years and oldersuffer from Alzheimer‘s
disease,

Other risk factors under study are
traumatic head injury, low education
attainment, early low linguistic skills,
high-fat and high-caloric intake, and
genetics. What scientists are now call-
ing “incipient“ Alzheimer‘s—the earli—
est onset of the disease regardless of
age—has been clearly shown to be ge-
netic in origin. Three genes, Markesbery
explains, account for less than 2 per—
cent of cases of those with early—onset
Alzheimer’s disease.

People in all of these at-risk catego-
ries may benefit from a study
Markesbery is currently heading up.
Funded by a $5 million grant from the
National Institute on Aging, the study
will pair vitamin E with selenium, an
essentialtraceelementfoundin allcells
and tissues in the body. Selenium is
found in water and food—seafood,
meats and Brazil nuts, for example.
Vitamin E is found in a wide range of
foods, especially vegetables, vegetable
oils, nuts, and egg yolks.

There ispriorevidencethatenhanced
levels of selenium in the brain might
increase antioxidant defense mecha—
nisms against Alzheimer’s disease.
Taken together, Markesbery says, these
two natural antioxidant supplements
mightworkbetterthan aloneinfighting

oxidative stress

“What is oxidative stress?“
Markesbery asks rhetorically. “Well, we
obviously need oxygen to live, but the
reactions that oxygen undergoes in the
body have to be carefully controlled or
else your body begins to produce oxy-
gen radicals that damage lipids. pro—
teins and DNA in cells, especially
neurons.“

This current project, which is called
PREADVISE (Prevention ofAlzheimer‘s
Disease by Vitamin E and Selenium),
will link up with SELECT (Selenium
and VitaminECancer Prevention Trial),
a large National Cancer Institute—spon-
sored study looking at the effects of
these two substances in preventing pros-
tate cancer.

The five-year PREADVISE study will
examine a subgroup of about 10,000 of
the more than 32,000 men being re—
cruited nationally for SELECT.

“Like prostate cancer, Alzheimer’s
disease usually occurs later in life, so
this study presents a unique opportu—
nity to assess the impact of selenium
and vitamin E on the beginnings of
dementia,” Markesbery says.

So far, more than 400 locations in the
United States, Canada and Puerto Rico
have enrolled men in SELECT. Study
investigators hope to recruit all the par-
ticipantsduringthefirstfiveyears ofthe
trial, so each man can be followed for
at least seven years. Five study sites are

located in Kentucky, including Central
Baptist Hospital in Lexington and the
UK Markey Cancer Center.

Men may qualify to participate in this
study if they are age (32 or older (60 or
older if of Hispanic or African origin)
and in general good health. Participants
must also have no history of diagnosed
dementia and no major head injury in
the last two years.

“Prospective participants take a men-
talstatus examination, and they have to
score in the normal range on that,“
Markesbery explains. “And there’s an
intake assessment where they're asked
alotofquestions, especially abouttheir
family history.“ Participants are then
placed randomly into one of four
groups: They get either vitamin E or
selenium, vitamin E and selenium, or a
placebo.

“We're in the very early stages of this
lZ-year—long trial.” says Markesbery.
“and the key right now is active recruit-
ing. Obviously the assessment of all the
data we get won‘t occur for some time,
but we will get updates along the way
on how we're doing."

The PREADVISE study is one ex»
ample, he says, of how basic laboratory
data from many Sanders—Brown studies
is being translated to preventive studies
in Alzheimer‘s disease. “You just can‘t
overstatetheimportanceofprevention.
This disease starts many years before it
ever shows up clinically."

 

 . mfiwWfile

: I _V , W :, haw "

Stephen Sr hell, a professor of anatorm and neurobiology

at l, k, is l()( using his work on mild (ognitiw impairment,

the earliest phase of memory decline

 

A New Focus on “Mild
Cognitive Impairment”

Detection of the earliest phase of
memorydecline has become soimpor~
tant that there is now a term used to
describe this fairly new research f< )cus:
mild cognitive impairment. or MCI.

“This phase is marked by memory
complaints that become more pro-
nouncedastimegoesby."sa_vsStephen
Scheff. a professor of anatomy and neu-
robiology at the Sanders-Brown Center
on Aging Several Sanders-Brown re»
searchers.Scheffamongthem.arenow
working to better understand MCL work
that is made possible by the UK ADRC
and its control group of Volunteers.
These participants, many of whom are
spouses or relatives of an Alzheimers
victim, are neurologically normal and
in the interest of science have volun-
teeredtobe research subjectsThecon-
trol group is headed up by David
Wekstein, associate director of Sand-
ers—Brown.

lnthisgroupofover~llitlpeopleabout
half are at high risk of developing
Alzheimer‘s becauseottheirfamilyhis-
tory—about 30 to 40 percent of cases
arethoughttobehereditarv.according
to Markesbery. Allofthesesubjectshave
agreed to donate their brains after they
die (see sidebar on p. 9).

“These participants undergo exten-
sive cognitive testing and represent a

 

 

  

unique resource for research into the
relation between neuropathologic
changes and cognitive performance in
aging," Scheffsays. He addsthat partici—
pants in the control group who show
significant cognitive changes or who
develop dementia continue to be ac—
tively followed by the ADRC.

“By studying this normal group of
volunteers, were getting closer to be—
ing able to detect the earliest possible
onset of the disease, and we believe
that with early preventive treatment,
we can slow the progression of the
disease," he says.

Scheff is among the vanguard of re—
searchers in the country involved in
this relatively new NIH initiative. “We
can learn a lot from looking at end—
stage Alzheimer‘s, but the focus has
shifted somewhat to trying to under-
stand what happens in early stages of
the disease." Working with Scheff at
Sanders-Brown are Frederick Schmitt
and Doug Price, who Scheff character-
izes as “an indispensable research tech”
who has been with him for 17 years.

Some of these control subjects will
begin to show some declines in cogni-
tive ability. “Typically, these are indi—
viduals who function normally all day
long," Scheff says, “but have a memory
problem in one particular area. It’s a
small loss of memory that might mani-
fest itself in, for example, delayed re—
call. and we can test this.“ A standard

way to measure possible memory loss
is to give the patient a list of words and
ask him, five or 10 minutes later, to
recall the list. People with MCI show a
deficit in delayed recall, Scheff says,
and some researchersbelieve this might
be the beginning of Alzheimer’s dis—
ease.

In addition to talking to people in the
controlgroup who report possible slight
memory loss, Scheff also gathers neu—
rological evidence of MCI. An expert in
brain anatomy, he has performed brain
autopsies for the past 16 years at Sand—
ers—Brown.

“I'm a neuroanatomist,” Scheff says.
“I’ve been teaching brain anatomy in
the College of Medicine here for over
23 years." He is part of the UK autopsy
team, which also includes Markesbery,
who collect particular pieces of tissue
thatresearchersneedto analyzeThese
tissues are used by UK researchers as
well as scientists at other institutions
around the country. “We're a brain
bank," Scheff says. “We store lots of
tissue, and we share it with otherADRCs
doing excellent research since we're
all working to solve the Alzheimer‘s
puzzle.”

Some of the brain tissue Scheff stud—
ies comes from people in the control
group who have been followed by Sand—
ers-Brown researchers for as long as 10
years. “We go back and review the clini-
cal charts and then combine this data

with what we see in their brain tissue.
We can then determine whether or not
the person had MCI."

Scheff closely studies the brains of
those who are determined to have had
MCI at the time of death, focusing on
what he calls “synaptic connectivity."

“You are born with essentially all the
neuronsyou‘re evergoingto haveWhat
develops is the connectivity, through
synapses, between different portions of
the brainYou havetrillions ofsynapses,
and you lose and regain them every
day—your brain is constantly remodel—
ing as you learn new things." Scheff
explains.

Early on in this work, he focused on
several areas in the cortex, association
areas that, like tiny assembly plants, put
together a lot of information. These ar-
eas are where higher-order learning
takes place,Scheffsays,andAlzheimer‘s
disease especially likes to attack these
parts of the cortex.

Usingstereology, a mathematical way
to estimate the total number of objects
using a 3—D model, Scheff can deter.
mine the number of synapses in these
association areas. “What we’ve found is
that in Alzheimer’s disease there is a
significant loss of synapses, and the
Alzheimer's brain doesn’t seem to be
capable of replacing these lost connec—
tions." Scheff, with several colleagues
at Sanders—Brown, has published pa-
pers extensively on this work.

 

  

More recently, he has focused on
another area of the brain—the hippo—
campus. This is the curved, elongated
ridge of brain tissue located behind the
ear that has long been thought of as
critical for memory.

“This is the area of the brain used for
learning and memory, and it's been in
the popular press a lot lately. We‘ve
gotten tissue from people in the control
group who have died, and some of
these individuals were tagged as hav-
ing mild cognitive impairment. In ana-
lyzing their brain tissue, we‘ve found
that people with MCI tend to have a
significant loss of synapses in the hip—
pocampus.”

Being able now to count and mea-
sure synapse loss is an importantstep to
understanding the mechanisms of
Alzheimer's, but even more important,
Scheffsays. is to learn why this degrada-
tion happens.

“We’ve been dealing with this re—
search challenge head-on foryears here
at UK,” Scheffsays. “We’ve looked at all
kinds of toxins as well as free-radical
activity. And a part of my work is to see

if there is a relationship between the
levels of free radicals and changes in
number of synapses.

Echoing Markesbery, Scheffsays that
prevention remains the key. What can
you do to keep synapse activity normal
and strong?

“Even though it’s true that the highest
risk factor for getting Alzheimer's is ag-
ing. we’ve found that if you are well
educated andyou take care ofyourself.
even people in their late 805 and 90s
don‘t show the loss of synapses and,
therefore, don’t necessarily get
Alzheimer's," Scheff says. “Everybody
used to think that if you live long
enough,you‘regoingtogetAlzheimer’s.
We don’t believe that anymore.

“The best way to keep your synapses
functioning normally is to keep your
brain very active—what I call ‘low-im-
pact mental aerobics.’ In the shower.
say your ABCs backwards or do a math
problem. Learn a foreign language.
Learn to play a musical instrument.
And keep as physically healthy as you
can.

 

How Do Enzymes Fit
into the Alzheimer's
Puzzle?

While Scheff is busy studying synaptic
connectivity. Louis I lersh is working to
better understand another kind of con-
nection: enzyme activity and aniyloid
beta (A-beta) protein deposits in the
brain. In dozens of projects both out-
side and inside of a living organism.
scientists in the past 30 years have
found that A-beta protein deposits are
a major component of senile plaques
in Alzheimer's-diseased brains. These
plaques and neurofibrillary tangles
(shriveled strands resembling bundles
of straw inside damaged neurons) are
strong signatures of the disease. Recent
data suggests that the A—beta protein
may also be toxic to cells before it
forms deposits.

So how do you stop A~beta deposits
from fm‘ming'.’

Hersh,professorand chairmanofthe
Department of Biochemistry in UK‘s
College of Medicine, believes that two
enzymes—neprilysin and insulysin—
might help do exactly that. “These two
enzymes have received the most atten—
tion as A—beta-clearing proteins," he
says.

Like firefighters off at the alarm bell.
enzymes marshal their forces when the
call comes. Their job is to move to the
sceneofaction as quickly as possibleto

 

 

 :.‘zugiwhiwtwifkfi‘flwfiim‘ ‘

 

   
    
 
 
 
 
 
 
  
 
  
  
 
  
 
 
  
  
 
  
  
 
  
 
  
  
 
 
  
  
  
  
 
  
  
 
  
 
  
  
 
   
  
    

start chemicalreactionsthe bodyneeds
to stay in balance and keep going. En-
zymes are enablers.

The most recent and compelling
evidence that neprilysin is an A—beta
regulator comes from research with
"knockout" mice. who have had this
enzyme removed. “In these mice, A-beta
peptide levels go up." says Hersh, who
has studied neprilysin for over 25 years
through a variety of projects. "We take
thisas evidence that neprilysin normally
breaks down these A-beta peptides, and
when the enzyme isn‘t there or
decreases in amount, the A—beta levels
go up, and that‘s not good." He adds
thatalthoughmicedt’m'tnaturallymake
amyloid deposits as the human brain
does ( which is probablywhy mice don’t
get Alzheimer's), many of the same
enzymes.suchasneprilysinare present
in both mice and humans.

lnsulysin has also shown itself in the
past few years to be a mighty A—beta
regulator, so Hersh‘s lab has turned its
attention to this first cousin of neprilysin
(both have a metal ion and contain
some zinc).

“Enzymes work on and break down
small molecules, and whatever an
enzyme goes to work on is called its
substrate," Hersh explains. “Forexample,
digestive enzymes work on many
substrates—think about the variety of
food you eat in one day." The A-beta

(UNI/I’Wt‘d on p H!

The BRAiNS Program

David Wekstein can’t ever count on a good night’s sleep.

“My phone might ring at midnight, at 3 am, anytime really.
And I have to be ready, along with other researchers here in the
ADRC (Alzheimer’s Disease Research Center), to get moving,”
says Wekstein, associate director of UK’s ADRC and Sanders-Brown Center on
Aging.

The most recent caller was a close friend of someone in the BRAiNS
(Biologically Resilient Adults in Neurological Studies) program who had just
died. Within an hour of the call, the body was on its way to the University of
Kentucky, where researchers immediately performed an autopsy. Both the
caller and his friend were part of a group of older Lexington-Fayette County
residents who have agreed to donate their brains after they die to help
researchers learn more about Alzheimer's disease.

Most agree to participate in the control group because they have personal
knowledge of Alzheimer’s. They‘ve lost a relative or a friend to the disease,
which afflicts an estimated 4.5 million people in the United States over the age
of 65, including an estimated 60,000 Kentuckians.

Jim Geddes, a UK associate professor of anatomy and neurobiology, says
that because the brain deteriorates so quickly after death, it‘s vital that an
autopsy be performed as soon as possible. “The support of family and friends
has been tremendous. We are often able to do an autopsy within three hours
of death,” Geddes says. “This does mean coming in at all hours of the night
sometimes, but luckily we have a dedicated group of neuropathologists and
researchers who do that."

Since it opened its doors in 1985. UK‘s ADRC has diagnosed and followed
hundreds of older people with non-treatable memory disorders—mostly
Alzheimer‘s disease. Wekstein has directed the BRAiNS program since its
beginning in 1989.

Butstudying the brains of Alzheimer's patients alone is not enough, Wekstein
says. “We can study Alzheimer‘s brains for the next 20 years, but if we don’t
study brains of people who don't have the disease, we can’t draw valid
conclusions.” This is why in 1989 he began recruiting people for a control
group. To date the center has recruited over 700 normal older persons, many
of whom are at high risk of developing Alzheimer's disease because of their
family history and other reasons. All of these subjects have agreed to donate
their brains at their death.

“The Sanders‘Brown brain bank is one of the most respected and highly
regarded in the country,” says UK pharmacologist Eric Blalock, whose re-
search is based on brain samples he receives from the ADRC. “Very few
Alzheimer‘s disease research centers have the kind of rapid-response team we
have?

For additional information on BRAiNS, contact Wekstein at 859/323-6040 or
at dwekste@email.uky.edu.

  

  

Louis Hersh in UK’s College of
Medicine is focusing his work on
two enzymes—neprilysin and
insulysin—that team up to clear
away dangerous amyloid beta

deposits In the brain.

peptide, it turns out, is a substrate for
insulysin, so insulysin and neprilysin
have a common enemy.

One very important recent finding in
Hersh‘s lab is that these two enzymes
work to stop A—beta in different but
complementary ways.

“The reason neprilysin has been so
widely studied is because it‘s one of the
few enzymes that work on the surface of
the cell, on the cell membrane. A-beta
peptides are secreted from the cell. So
neprilysin can go to work on A-beta as
it's being secreted or as its beginning
to travel into extra—cellular space."
lnsulysin, on the other hand, works in—
side the cell, so there's a sort of tag—
team approach to stopping A-beta in
its tracks.

lt used to be thought, Hersh says, that
as we age we overproduce A—beta, that
it overwhelms the cell. There is evi-
dence now to the contrary.

“We're starting to believe that rather

10

than an overproduction. what‘s hap-
pening is an Under-clearance,” says
Hersh. “The activity of the enforcer en-
zymes is somehow lessened, which al»
lows the damaging effects of A—beta to
go relatively unchecked."

This realization has moved Hersh's
work into a new direction. he says.
With continued funding through the
Alzheimer‘s Association and the Na-
tional Institute of Aging. he's looking
now at various ways to increase the
activity in the brain of these two key
enzymes.

“We've never lost sight of the poten-
tial Clinical applications of what we're
doing," Hersh says. “We're looking at a
number of approaches to utilize these
enzymes to break down A-beta both in
the brain and elsewhere in the body.
We're just starting work with a biotech
company to screen chemical libraries
to see if we can find drugs that will
activate insulysin. That‘s what I'm most

 

excited about right now.” Hersh hopes
this research will lead to clinical trials
in about five years.

JeffreyKellerneyerthrMighthisyears
of research training would lead to an
intense study of garbage. but. he says.
that‘s just whats happened.

"Cells. like people. generate gar-
bage, and all cells have to remove it.
In order to keep this clutter at a non-
dangerouslevel.cells relyon onepar-
ticularintracellularenzyme.calledthe
proteasome." explains Keller. a i'lx'
assistant professor of anatomy and
neurobiology whose research at Sand-
ers-Brown is focused on understanding
theworkofthisessentialenzymeThink
of proteasome as the cell's chief gar.
bage collector.

The garbageunderscrutinyismainly
oxidized or mis-folded proteins. and
since accumulations of this substance
have been implicated in Alzheimer's
disease, Huntington's disease and
stroke. Keller's research might help pro-
vide important clues to the etiology of
these diseases

Scientists think they have a handle
on what the enzyme generally does but
very little is known about the exact
expression of proteasome activity in
the normal and diseased brain, and
even less is known about the possible
role of proteasome inhibition in cell
death. says Keller. who spent one year

 

 as a postdoc at Sanders-Brown after
earning his doctorate here in molecu-
lar and cellular biology in 1998.

"Our lab is trying to understand ex-
actly what the garbage disposal in the
brain looks like when its operating
normally and what it looks like when it
goes bad. ln addition. we're interested
in understanding what causes it to stop
functioning normally as we age. or in
age—related disease."

In his studies Keller uses basic mo—
lecular techniques. called the reverse
transcriptase polymerase chain reac—
tion (or RT PCR). in cellular. animal
and human tissue.

“Using RT PCR. we are able to visual—
ize or quantify the expression of iridi—
vidual proteasome subunits." Keller
says. “This is a common way of investi-
gating gene expression. When we
couple this with our ability to isolate
and purify the proteasome enzyme. we
have very powerful techniques for ex—
ploring the proteasome in aging and
age-related disease."

In this work. he and his co—investiga—
tors are utilizing yeast. which, he says.
looks a lot like human brain tissue.
“Remarkably. the pattern of proteasome
expression and the process of oxida—
tive stress are similar in yeast and hu-
man tissue. The advantage of using yeast
lies in the power of genetics—we can
rapidly and directly test the role of spe-
cific genes in regulating the proteasome

    
 
 
 
 
 
 
 
  
  
 
  
  
  
 
  
  
  
 
 
  
  
  
 
  
  
  
 
 
  
  
 
  
   
   

and its toxicity in a matter of days instead of months. We can
then apply this knowledge to the animal models of disease.
and even the actual tissue from human disease."

Keller admits that this approach is extremely challenging.
not because of their methodology but because of what he
calls “the numbers game,"

“Proteasome is so complex. At its heart. it's a structure
made up of 28 different proteins. There are at least 82
additional proteins that can combine in different ways to
comprise this 28-protein complex. Every cell has a smorgas—
bord of choices to assemble its garbage disposal." The
bottom-line goal of this work. he says, is to differentiate the
changesthatoccurwith normalagingfrom the changes that
occur with Alzheimer’s disease.

Keller says his lab is making good progress in “getting
proteasome to give up its secrets,” and that any success is
due to the various collaborations in the Center on Aging:
Allan Butterfield (chemistry and Center of Membrane Sci—
ences), Harry Levine (Center on Aging), Rodney Guttman
(gerontology PhD. program), and Jim Geddes (anatomy
and neurobiology). “They‘re experts in different areas of
neuroscience, and we are able to apply their skills to our
project. And of course Dr. Markesbery, who’s at the center
of all of the work we do here," Keller adds.

Keller is at the halfway point in this work, which is being
supported by the National Institute of Aging for $1 million
for four years and by other grants from the National Insti-
tutes of Health and private foundations.

   

  

 

Microarrays: Chipping
Away at the Mysteries
of Alzheimer's Disease

Genes, like enzymes, are also role—play-
ers, and molecular biologists continue
to spend long hours in the lab working
to shed light on these various roles.
Traditional methods in molecular biol—
ogy generally work on a tedious one-
gene—in—one—experiment basis, which
does not allow for a whole picture of
gene function. However, advances in
technology are now paving the way for
biologists to study genes on a much
larger scale.

“In the past several years a new tech-
nology, called DNA microarray, has
revolutionized how we do gene re—
search,” says Philip Landfield, profes-
sor and chairman of the Department of
Molecular and Biomedical Pharmacol—
ogy in the UK College of Medicine. An
array, he explains, is an orderly arrange—
ment of gene pro