Mitochondrial abnormalities in Alzheimer disease

S213

cstradiol’s

protective

pathways

that

ectradiol

exerts

effects.

may

We are exploring

be involved

profound

with

possible

estradiol’s

neuroprotective

second

mesw~ger

protective

actionr

in viw

effects.

In

signaling

double-blind,

summary,

to moderate

vitro.

and in

affect

placebo-controlled Alzheimer’s

global,

Panicipants CONTROLS IN

BRAIN

ABETA

LEVELS

PLAQUE-FORMING

IN

TRANSGENIC

was

the

of mood,

living.

global,

Assessment

Overall,

cognitive

is justified

Several

epidemtologvzal

onset

of

dementia

studies

Alzheimer’s

i\ not supponed.hy

share the common r\trogen

(E2)

indicate

disease

might

(S.P..

D.F.,

S.G.),

of total

brain

abeta were elevated

to gonadally-intact

(I 3fold

average for

p.o.

associated

or functional

independent

in brain

set of

when

Variance

aheta

amyloidosls

was also increased

ohaerved

during

initiation

of deposition

could

of

began earher

these two studies

clmicnl

of amyloid

neuropsychological

in ovxed

prior

visually

of the ovxed

the

aheta

levels

were

PSlAPP

mice

to the accumulation

mice,

and

typical

long

that

cham ovxed

i.e., before

probably

@@

ALZHEIMER’S

the

mice.

status plays

and/or

before

during

a

the

the onset

of

TREATMENT

TRIALS

IN

DISEASE

are ten caw-control

c~aluarr wme

the assocutmn

wggeht

wggest

oddr

developing

of 0.71(95%

evidence

improve

wggesting

cognitive

trials;

compared

to placebo

and

potential

side

the

disease,

venow

recommend modulatorc

have

to raloxifene

decline iRR=O.77;

on

awgned

Trails

A

95%’ Cl

Whether

raloxifene,

cognitive

decline,

on breast

Cell bodies peroxide

and

0.86:

0.59-1.00)

95%

but

or other SERMS, further

not

health

(968) MER’S

OF

A

AD.

Only

there

damage

I

In

in

cancer).

it

selective

the

of 7478

SER,MS.

of developing

Cl

0.74-1.01)

on

4 tests severity,

and

postmenopausal

a lower

and

to

receptor

and lipids

had

risk

of

evidence

i% premature

completed.

IN

form,

portion

procedure\

in the area covcrrd in AD

with

ahnormalltie+

mtDNA

energy

l’ailurc

to delay

ALZHEIMER

tAG09827,

the nruron\

Health

to the

perikaryon,

portion

investigated

found

obtained

yr),

from

we found

of the hpofuwin

together,

il significant

and dccl-ca\r

is highly

these finding\ change\

from

by the AlLhzlmer‘\

death.

Suppo~ced

Foundation

that

in metnboli\m

and the National

m

correlntcd suggest

leads to compenwtory

Assistance

as the

wa\ mostly

specimen\

acid oxidation

Taken

we

type, a\ well

the mtDNA

50.84

of nucleic

display

in the AD case% but only

biopsy

age\

hpid

Oxidative

or not the neurons

increacrd

brain

hy the vacuolu

in AD

oxidation.

in the latter case by 40.60%.

analysis,

In

and 6 controls.

level

have increased

acid

at this site. Wild

greatly

(r’ = 0.87).

of neurons

American

wa\

lipofuacin.

cases. The

of protecting

ation.

of damage

By ultrastructural

(8 AD

(AD)

nucleic

reduced

ahnormalitie\

mtDNA

of

dint%

and

and is seen whether

rertriction

mmxhondru

as a A\wcl-

Institute\

of Health

AGl4249).

AND SELECTIVE

IN TRANSGENIC

MICE

to

cognitive List

Recall

(unpublished

i\ a type III intermediate

associated

IALS).

To

data).

or slows age-related

TRIAL

IN

support

ALZHEI-

disease in women.

to investigate A randomued.

with

DEATH

OF MOTOR

OVEREXPRESSING

NEURONS

PERIPHERIN.

mice

periphcrin

in mice caused

light

(NF-L)

augge\t NF-M

the

of IF ~ncluvon

and NF-H

the mechanism

of NF-L.

can interact

peripherin

inclusions

were

superox&

dismutase

(SODI)

whether could

established wch

bodies

IF inclusion\

with

also

detected

associated

m motor

may play

to form

in

with

inclusions

neurons

of ALS

a contributory

role

mice

inhihitory

remain

While unclex, mutant

mutant

SODI

and

gene expwxion. by inflammatory factor

the prr\rnce

and our results

in pathopeneais.

rev& protein

i\ now it) pmgrr\\

is upregulated

explain

patients

Our

cxprcwng

Work

in mice expressing

may

death

IF aggregates.

aggregate\

ALS.

ALS.

neuron

ALS.

Icvels of peripherin

and leukemia that

in human

neurofilament

noxious

of

character-

of neurofilament

sporadic

tranagrnic human

gene expression (IL-6)

tound

hy a deficiency with

level\

divzaw

and the onset of motor

by peripherin

enhanced

I\ one mechanism

thox

wlero\is

we genet&txl Exe\\

neuron

molecular-weight

peripherin cawed

that peripherin

penpherin.

aswciated

death

from

mouw

precipitated

the high-

the perlpherin orIginate

as interleuku-6

intlammation

wa\

of pcriphcrin.

motor

of u~cluw~n

lateral

effects

I-ewmbling

bodies

a phenomenon

of ncuronal

ALS

bodies

in the majority

in amyotrophic

und relective

of IF inclmion

overexpression

protein,

that. m abwnce

in human

the wild-type

a late-onset

the cormation

neurons

detrimental

that overexprr\\

by the prewnce

Remarkably.

(IF) detected

motor

the potential

tramgenic

lred

filament

degenerating

inve\ttgate

due to periphcrin

Compared

Word

Puipherin bodies

inclusion

of Alzheimer’s

the

at risk of death.

vacuolar

dlagno\tic

fore,

for the treatment

of estrogen

for AD.

estrogen

on bone

A trial

studies provided

neurons

of

carhonyl<,

and. in fact, are actually

LATE-ONSET

gallbladder

was recently

TREATMENT

among

Skb-deleted

cytokines

role of estrogen

investigation

and as a mean?

of Neurodegeneration

of death m Alrheimer free

there are mitochondrial

is well

and epidemiological

of

it improve

three were

widely-recognized

other

at rirk

tangles

consideration

whether

and

DISEASE

Basic science, clinical

treatment,

ABNORMALITIES

nitration,

uniform

Epidemio-

was no benefit

abnormalitier,

moht

a

study.

RECENT

Mechanisms

of neurons

to drtermme RESULTS

nor did

The study does not support

of thih disease. Further adjuvant

other

activities

scores on several but not

propertw

on the

progression

in these women.

various

and

risk of

of AD

on this conflicting

breast

reduces dementia

disease

and

function

importance:

as a treatment

with

Recently.

uterus.

outcomes

motor

the

dixzuse

adduct\.

neurolibrtllary

mran’~

others

reported

standard.

development

improved

The

or placebo

to raloxifene

(RR=

require?

and

been developed.

effect?

women

prevent m estrogen

have estrogen-agonist

women

public

to

therapy:

while

studies

the gold

(endometrial

event\.

AD

a 29% decreased

for women

two reported

of estrogen

estrogen-antagonist placebo,

interest

he used to treat AD.

and ralomfene,

random&d

remain

use may

estrogen

observational

suggesting

scales and one concluded

thromhoemholic

(SERMS)

tamoxifen

of

on any of the scales. Baxd

effect\

that estrogen

and

0.98)

triala of estrogen

cognitive

estrogen

(AD1

trials

has sparked

placebo-controlled

all of the administered

d~\ewz

on development

users. Thts may be of major

that estrogen

function

that have been conducted

of ten of thew

placeho-controlled

are six, Emall published

randomiced

of estrogen

Cl 0.52

estrogen

randomized

\tudie,

Al/heimer‘\

effect

A mrta-analytic

ratio

AD among

however,

There

between

a protective

no effect.

w~~rnary

logic

and two prospective

not slow

(9691 MITOCHONDRIAL DISEASE

increase

There

Subscale),

for the treatment

Symposium:

common

AND

Cognitive

in

Scale), the ADAS-Cog

of

of values

suggesting

that estrogen

accumulation,

EPIDEMIOLOGY

Scale

outcome

Included

In an

change\.

OF

Rating

in the areas of prevention,

111neurons REVIEW

Dementia

language,

primary

ovx-

p
mice than in control,

therefore

The

change).

time.

by immunocytochemistry).

the conclusion

amyloid and

brain

of

of

and were

I or 5 mg/kg

reverxd

plaque-forming

amyloidosis,

support

deposttion,

total

(i.e., one month be detected

visualtzable

role in the early stages of cerebral initiation

L.R.), m owed

ah

was also elevated

decrease;

points.

period

YS placebo,

pig\.

p
pigs with

partially

average

in the aheta values

initiation

‘Taken together,

J.S.,

elevated

was incipient

that deposits

ovx)

(20%

S.P.,

(p
of ovx guinea

after

levels

atudies,(K.D.,

to be significantly

abeta to the extent

Treatment 8 weeks

year

set of

of guinea

increase,

The aheta 42/ aheta 40 ratio

p
(beginning

AD

whether

In the first

(ovx)

average

time

impression

mild could

or delays

and sporadic

metabolism.

month

a one

of estrogen

with

therapy

established

we invtxtigated

ovariectomy

(1.5.fold

of

of famdial

amyloid

following

animals.

mcrease,

IO day\ increase

observed studied

ten weeks

prevent?

treatment

amyloidosis,

alter cerebral

levels

E2

replacement

estrogen

such data. Since all forms

wdies

compared

while

of enhanced cerebral

feature

deficiency

that estrogen

(AD),

did

over

replacement

(Clinical

attention,

estrogen

onset of Al/heimer’:.

the

I2

global

in 120 women

if estrogen

two dosages

and

(clinical

memory,

the role of estrogen

was conducted

decline

between

were the CDR

Disease

measures

trial

functional

6 month,

CGIC

measurer

(Alzheimer‘s

daily

or

at 2 month,

measure secondary

MICE.

cognitive

were randomized

evaluated STATUS (9661 ESTROGEN GUINEA PIGS AND

clinical

Disease to determine

(LIF).

There-

of pcl-ipherin

suggest

that uch

It