A new family with Gerstmann-Straussler-Scheinker disease with a mutation of codon 232 (met to THR)

A new family with Gerstmann-Straussler-Scheinker disease with a mutation of codon 232 (met to THR)

s122 Poster PRECURSOR 1550).AHYLOLD ATED PROTEIN TAU, PROTEIN, MICROTUBULE ASSOCIAND UBIQUINATED INCLUSIONS: BRAIN AND SPINAL CORD PATHOLOGY OF VAR...

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s122

Poster

PRECURSOR 1550).AHYLOLD ATED PROTEIN TAU,

PROTEIN, MICROTUBULE ASSOCIAND UBIQUINATED INCLUSIONS: BRAIN AND SPINAL CORD PATHOLOGY OF VARIOUS TRANSGENIC MICE

1553) PATHOLOGIC AGED RHESUS Chnngb lsruel

Grula,

Edwin

Chen, Annelies

Med

Cent / Harvnrd

Deaconess

Recent observations

from

brain may be selectively Formation

of intracellular

disease. Specifically,

inclusions

Alzheimer‘s

disease (AD)

large aggregates of Alzheimer’s aggregates

of tau protein.

characterized diamutase

precursor

Familial

by the formation

protein

1s a common

(SOD)

and

ubiquitin.

pathological

state in various tranagenic

In

in these pathologies,

ApoF.4, and the mouse model for FALS

in the spinal cord. Specifically,

microglia.

lateral

sclerosis containing

order

understand

to

are also engineered

which consists of a SOD1

is also

the ruperoxide any

common

tramgene.

of relevant cellular

we have followed

we have examined

of the

as an increased understanding

pathological

state. A deeper understanding

intervention

opportunities

mice

We have

markers in brain and

the distribution

the parallel

of

with the AD risk factor

of ubiquitm.

activation

The analysis of these data reveals common pathological

two diseases, as well

(FALS)

inclusions

Injections

and separate

we have studied the progression

a time course of mlmunoreactivity

APP. and tau. Moreover,

by the formation

and ubiquitin,

mouse lines. These mouse lines include:

transgenic for APP, tau. APP mice which

examined

(APP)

amyotrophic

involved

of neurodegenerative

is characterized

protein

of intracellular

mechanisms

hallmark

SODI,

of astrocytes and mechani,ma

in the

of the earliest appearance

of the

of the progression

may present novel windows

of the disease and early

for therapeutic

neuronal

loss, phosphorylation

be of relevance abnormalities

piJ Jowf

Pm?:i.

CITY,

IA

Gory

W Vm

Hor.ren.

Armnio

R Dnmnsio.

Univ

OF

IOWA,

IOWA

of all five animals. morphology

of

S-positive,

acetylcholinesteraae

the aged rhesus contained subpopulation

The periaqueductal

gray matter (PAG)

It has pwotal

in the processmg of emotions

roles of this structure contribution

is relatively

of PAG

dyrfunction

has not been considered. compromised

of AD.

contained

major

in all

26 control

absent

dementia rically;

patients).

functions,

and feelings.

behavior,

component

of the

and cognition

most

The elucidation

to the manifestations

of Alzheimer’s

we demonstrate

the possibihty

that PAG

that PAG dysfunction

disease (AD) IS selectively

may contribute

pathological

change\ (13

in 81%

from

of casts. These changes were

normal

subjects

and

In the AD cases, both sides of the PAG

IOD5c,

ALZ-50

(NFI’s).

and AT8 anttbodies,

and abnormally the type

tangles

phosphorylated

and the density

13 from

non-AD

were affected

symmet-

PAG regions and correlated

findings

provide a first

pattern of AD

humans the columnar experimental

15521

organization

Poland;

with

changes

Furthermore,

Acud ofSci.

Lurisu

were

expressed

of brainstem

Wmww

the selective

changes in PAG

primarily

in

These

in AD

in association

Mnriu

Poland;

Jolunta

Bratosirwicz.

NIH,

Bethesda,

MD;

polymorphic

wa,

performed.

codon

in AD.

Anne K Vrhmas.

Cluudia

Wulter

Johns

Stewurt.

Tmwoso.

There

phenotype.

for

Paul

Mrd

Brown,

National

Lad,Inst

of

multicentric

genetic

gene by sequence, nucleotides.

plaques revealed “hybrid

repofled

analysis

components

the same chemical with

loas of

AP deposits

Clq

and C3d.

effects were observed indicate

that

signatures as those

many of the pathologies

tangles. Our findings

observed

also suggest that the

was linked

phenotype

of inflammatory

brains

from

classification,

I1

with

for microglia

Inc.)

cawed

by

we measured

2.7%

in possible AD,

only slight difference

significantly

higher

AD

and 1.4%

immunoreactivity demented

cases (p
early

cognitive

AD.

decline.

restriction

to

dementia,

at

dementia.

endonuclease exam-

in a codon where another

with Creutzfeldt-Jakob

disease

controls AD

These

while

astrocytes

tau immunoreactivity

antibody)

and

for each

was negligible

and possible (p
dichotomy

AD

F.A.

in

(4.2%),

for

in controls,

1.2%

not significant.

Tau

between

non-demented

was

observed

only

deposits

but are not sufficient

and microglia

but

HLA-DR

wa\

suggest that A-beta

most likely

Moreover

between astrocytic

neuritic

immunastained

AD. By contrast, F.A. for GFAP

this increase

of A-beta.

(normal

of immunoreactivity

(5%)

of the disease,

AD with

System (MicroBright-

the subject-sets (0.8%

observations

in the presence correlation

(demented

area for A-beta

(9.3%),

AD),

the

to the CERAD

depostts (Athena

as tau immunoreactivity

Activated

significant

Neuropathological

A-beta

in definite

sharpest

in the pathogenesis

statistically

triplet

between detinite

To study the

15 had possible

area (F.A.)

and 5.2%

the

According

AD

in the

we exammed

were single and double

Fractional

in definite

revealed

ADRC.

controls,

showed a gradual increase between

in possible

of the PRNP

open

in

component

Using a Stereo Investigator

the fractional

C

are immunocompetent

changes in AD,

and 9 had definite

gray matter.

MD;

Juan

MD

and microglia

the JHU

normal

MD:

in the presence of A-beta.

astrocyte? (GFAP),

controls. showed

were

Anti-tau).

in the cortical

effects

codong

AND COG-

Baltimore.

Baltirnow.

immune/inflammatory

sections of the neocortex

antibody

was

Bnltirnorc,

are neurotoxic

plaques)

(HLA-DR),

Health.

reaction with cognitive

subjects

Tau protein (Monoclonal

Srh of Medicine.

Public

astrocytes

3.5 subjects from

neuritic

Paraffin

oj

for a chronic

In the CNS,

cells. and these cells in vitro

synergistic

of the codon 232 (Met

IN SENILE PLAQUES

Johns Hopkins Sch

Sch of’ Medicine,

evidence

of AD.

plaques. The family

plaques” composed of PrP and

case with a new mutation but which

Scheinker

H Kawa. Hopkins

Hopkim

is growing

pathogenesis

plaques).

Research

Med Acud Lo&.

the MethionineNaline

with allele-specific

This is mteresting

Imutation wa\ already

Johns

The

only been shown m

Burcikowska,

We found a new mutation

129 of the PRNP

ination, besides PrP amyloid [email protected] peptide.

Molecular

was heterozygous

and hybridization

significant

axons was as high as 26.34%

AP deposits. These observations

IMMUNE REACTIVE CELLS 1554) NITIVE DECLINE IN AD

neuropil

apparently

patient

dtsplayed

A

neu-

AB.

cognition

MD

history

frame

dystrophic

aged primate brain is a suitable model for the direct study of the pathology

reactivity Polund;

by abundance of PrP-immunopositive

analysir

with compact

in the absence of neurofibrillary

and

also reveals for the first time in

We report here a case of prion disease of Gerstmann-Straussler-

The

plaques

The above pathologic

AP deposits in the aged rherus brain contain

autopsy

changes of PAG

Lad:

negative.

by astrocytes.

tau itmnunoreactive

many

and apoli-

of [email protected] deposits in

and were surrounded

for the complement

the presence of inflammation.

differently

WITH GERSTMANN-STRAUSSLERWlTH A MUTATION OF CODON 232

characterized was

activity

A Number

axons. The loss of cholinergic

(had

AP deposits in the aged

with areas a short distance removed from plaques. Many

appear

Thr).

microglia

had the

thioflavin

sheet conformation

many

immunoreactivity

correlation

nuclei

of PAG, which has previously

Led:,

Cervenokoru.

Herr/t/~, Bethesda,

reading

a P-pleated in AD,

were

also contained

field.

Med Acod

plaques

when compared

we found that

animals.

P Libervki,

Ctr, Polish

methods

with gender and the duration of dementia.

A NEW FAMILY SCHElNKER DISEASE (MET TO THR)

Puwel

in the PAC.

for the involvement

step in documenting

compartmentalized

immunohistochemical

we also established the presence of beta amyloid

tau protein

different

constitute

Using

of pathological

new evidence

A subpopulation

of

to

S, the

in 72% of AD cases there were only senile plaques (SPs), and in 9% both SPs

nemofibrillary

20%

hyperphosphorylated

indicating

the above

of the functional

In a study of 32 AD brains stamed with thioflavin

brains

(AD),

recent and perhaps because of that the possible

In this article

m AD and raw

the manifestations

and

is a major neuroanatomical

roles in autonomic

disease

and butyrylcholinesterase

area surrounding

in the cerebral

with native A!3 deposits. Here

immunoreactivity.

enlarged

displayed

Nearly

to plaques

E and ul-antichymotrypsm

peptide.

A!.3 deposits in the cerebral cortex of five

had attained

Similar

(AP)

pg) caused Eignificant

plaques were present in the cerebral cortex

deposits.

that AP

into tibrils).

Beth

effect in the aged rat. To

of Alzheimer’s

found in AD and that they can be awxiated

brainstem.

PAG

AD

Gonzalo-Rub,

proliferation

Most plaques were of the diffuse variety.

compact

rhesus displayed poprotein

(200

were without

in association

effects of individual

IN THE

MA

AP

of tau and microglial injections

II

that neurons in the aged primate

of fibrillar

AP immunoreactive

indicating

transformed

in AD,

notably

indicate

to the pathophysiology

we describe pathologic

Aliciu

Med Sch. Boston.

must also be demonstrated

aged rhesus monkeys.

Sepehr Smi,

DEPOSITS

to the toxic effects of the amyloidp

cortex of the aged rhesus. Similar

neurons and cholinergic

SELECTlVE PATHOLOGICAL CHANGES OF THE PERIAQUEDUCTAL GRAY IN ALZHEIMER’S DISEASE

Klink,

our laboratory

vulnerable

Neuropathology

OF AMYLOIDB

of very small concentrations

rites. The immediate

intervention.

EFFECTS BRAIN.

Presentution:

and in the in AD

to cause

have neurotoxic

the data demonstrates

reaction and the development

appears as a strong morphological

correlate

a of of