destrooper2

(1)

De ziekte van Alzheimer

Stand van de wetenschap en toekomstperspectieven

b

(2)

1. Dementie (wat, vormen)

2. Statistieken, kostprijs (Pacolet, HIVA)

3. Wetenschappelijk onderzoek (wat gespecialiseerd)

4. Een woordje over de acetylcholinesterase inhibitoren

(erg duur, relatief weinig effect)

5. Experimentele therapie (de toekomst)

(3)

Dementie

I. Meerdere cognitieve stoornissen

A. geheugenverlies (amnesie)

B. één of meerdere van de volgende cognitieve stoornissen

(afasie, apraxie, agnosie, stoornissen in uitvoerende functies)

II. Achteruitgang van het sociaal en beroepsmatig functioneren

III. Progressief verloop van de ziekte

IV. Mogelijke bijkomende symptomen

(4)

De progressieve achteruitgang.

Kleine geheugenstoornissen (jaar 1)

Grote geheugenstoornissen

Sociaal onaangepast gedrag

Hulpeloosheid

Afhankelijk voor basisbehoeften

(5)

Pseudodementie

Depressie

hoor/zicht

milde cognitieve

stoornis

Schildklier

bloedarmoede

vit B12

geneesmiddelen

alcohol

Pick

Parkinson

Huntington

(6)

Diagnose

Anamnese

Medisch onderzoek: klinisch

neurologisch

Complementair psychiatrisch en/of

neurologisch onderzoek

(7)

De ziekte van Alzheimer

“Uber eine eigenartige Erkrankung der Hirnrinde”

Alois Alzheimer (1907)

Algemeine Zeitschrift für Psychiatrie und

psychischGerichtliche Medizin (Berlin), 1907

(8)

Statistiek:

-

110.000 gedementeerde patienten in België

+70.000 met AD

- 4 miljoen AD patienten in USA

- gemiddelde overleving 8 jaar, soms tot 20 jaar vanaf eerste symptomen

-100 miljard dollar/jaar in de USA

-+/- 1% van het BBP in België; (1.78 tot 2.81 miljard Euro)

-178.000 Euro/patient/jaar

(1972 Euro/week)

0

2

4

6

8

10

12 <59

59-69

70-79

80-89

AGE

%

women

men

prevalence

(9)

Hoe deze ziekte bestuderen?

(10)

Cholinesterase inhibitors:

Cognex (tacrine); Aricept (donezepil), Exelon (rivastigmine)

and Reminyl (galantamine)

Matig actief: werking in

Minder dan helft van patiënten

Enkele maanden vertraging van de aftakeling

Neveneffecten: matig, soms:

(11)

Erfelijkheid

Base-paren, DNA, genen, chromosomen

Aminozuren, eiwitten, structuur en

Functie

(12)

Hoe deze ziekte bestuderen?:

3. De moleculair-genetische of biotechnologische benadering (1980-…)

Neurale kluwens

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-40

Aβ

_1-40

Amyloide plaque

(13)

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-40

Aβ

_1-40

Aβ

_1-42

KM DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK

40 *

* *

*

1 (Edmann degradatie)

(14)

De βAPPtisten versus de TAUoisten

(15)

Vragen

Aggregates

Aβ

1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-40

Aβ

_1-40

Tangles

1.

2. Dysfunctie neuronen+toxiciteit?

3. Oorzaak en gevolg?

(16)

Genetica van de ziekte van Alzheimer

familiale versus sporadische vormen

Gene

APP

Presenilin 1

Presenilin 2

ApoE4

chromosoom

21

14

1

19 early and late

start

early

opmerkingen

Down’s syndrome

Risk factor

0.05% of all AD

(17)

KM DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK

KM

NL

β1

β11

α

_*

γ

40 γ

42 L

P

A

G

E

Q

G

1

11

16 19 2122

40 42

Bace2

I

V

*

* *

*

V

I

F

G

L

M

V

67

0

69

3

70

9 Bace2

72

4 γ

₄₉

h

β-secretase

_α-secretase

_γ-secretase

h

V

T

I

(18)

The amyloid cascade hypothesis

voor de ziekte van Alzheimer

Aβ

APP

Swedish, Flemish

London, French, Florida

Austrian

Presenilins

Protofibrils?

Aβ

_1-40

Aβ

_1-40

Aβ

1-42_1-42

Aggregates ?

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-42

Aβ

_1-40

Aβ

_1-40

(19)

β-Amyloid peptide Precursor Protein

=APP

1. Aβ peptide van de plaques

2. Down syndroom en Alzheimer

3. Genetische mutaties in APP gen

4. Alle mutaties veroorzaken veranderingen in de

verknipping van het APP eiwit

Maar verklaart slechts 0.05% van alle gevallen van AD;

Geen verklaring voor Tau-neurale kluwens

(20)

N

C

The presenilins in Alzheimer’s Disease

Aβ

KM

TVIVITLVML

1 16 40 42 671 717 723 DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA 49

Lumen

Cytoplasm

(21)

Het probleem blijft:

1. Relevant voor slechts klein percentage van AD gevallen

2. Geen inzicht in het mechanisme

3. De oorzaak-gevolg kwestie

Aβ inbrengen in hersenen?

Proeftherapie?

(22)

Proefdiermodel

-COOH

APP695

Aβ

Thy-1 promotor

polyA signal

βA4 βA4 βA4 βA4 βA4 βA4 βA4 βA4

Doel: 1. Nabootsen van de pathologie:

Plaques + kluwens + geheugenstoornissen

(23)

LONG-TERM POTENTIATION

HIGH-FREQUENCY STIMULATION

rat hippocampal slice

S: stimulation of Schaffer collaterals

R: field excitatory postsynaptic potentials (EPSPs)

(24)

Prof. Rudi D’Hooghe

• •

TRIAL 1 TRIAL 8 TRIAL 16

MORRIS WATER MAZE

• •

Acquisition

TRIAL BLOCK 1 2 3 4 ES C A PE LA T E N C Y ( in s ) 0 50 100 150 200 250 300 350 400 % T IM E IN QU ADRA N T 0 10 20 30 40 50 60 target adjacent 1 adjacent 2 opposite

(path length, swimming velocity)

(target entries)

Testing

(probe trial)

(25)

Een voorlopige balans van de genetisch-biotechnologische benadering:

(1987-2001)

1. Een reeks spelers: APP, Presenilines: generatie van de amyloide plaques

2. Eén risico factor: apolipoproteïne E4

3. Een consistente werkhypothese: de amyloid cascade

4. Een mogelijk verband tussen plaques en tangles

5. Een redelijk proefdiermodel voor de ziekte

1. Wat veroorzaakt de neuronale dysfunctie en uiteindelijk de geheugenstoornissen?

2. Kan er therapeutisch iets gedaan worden voor de patient, wat is het tijdsperspectief?

(26)

Aggregates ?

Aβ

APP

? Protofibrils

Aβ

1-40

Aβ

1-40

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-40

Tangles and cell death

Aggregates ? Aggregates ?

Aβ

APP

_Aβ

APP

? Protofibrils

Aβ

1-40

Aβ

1-40 ? Protofibrils

Aβ

1-40

Aβ

1-40 Protofibrils

Aβ

1-40

Aβ

1-40

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-42

Aβ

1-40

Aβ

1-42

Aβ

1-40

Tangles and cell death

Production

Secretase-inhibitors

Vaccination

Toxicity

Inflammation

Neuronal dysfunction

(cholinesterase inhibitors)

Clearance ?

(27)

Hong et al., Science 2000

Beta-secretase

SP

Pro

DTGS DTGS

(28)

Het γ-secretase complex

N C Asp257 Asp385

Presenilin

Nicastrin

N

APH1

PEN-2

PS1+/- PS2-/- PS1-/- PS2-/- PS1+/- PS2-/- PS1-/-

precursor cel

NOTCH

(29)

NOTCH

S1 S2 S3

APP

βα γ

Presenilin

ADAM

Regulated Intramembrane Proteolysis (RIP)

precursor cel

(30)

Dale Schenk, Nature 1999

A β

(31)

Vaccination:

ELAN and Wyeth

1. Preclinical tests in mice: ok

2. Phase 1 (80 volunteers): ok

3. Phase 2a: 360 patients: trials stopped after 1 year:

Aseptic meningoencephalitis

clinical improvement/stabilisation in a few patients

(Hock et al, Neuron 2003)

(32)

Side effects, mostly at the level of gastrointestinal tract

upon prolonged treatment

--Reduced risk of developing AD in patients Reduced risk of developing AD in patients

treated with

treated with NSAIDsNSAIDs

--SpecificSpecificinhibitioninhibitionof of AAββ₁₁_-_-₄₂₄₂generationgeneration

--Decrease inflammation in the brain Decrease inflammation in the brain

that contributes to neuronal loss

--Inhibition of AInhibition of Aββ₁₁_-_-₄₂₄₂generationgeneration NSAIDs

NSAIDs

--Risk of autoimmunity and brain inflammationRisk of autoimmunity and brain inflammation

--Antibodies might not cross the bloodAntibodies might not cross the blood--brain barrier in humans brain barrier in humans

as they do in mice

--immune response might not be efficient in older peopleimmune response might not be efficient in older people

In mouse models for AD:

--decrease in decrease in amyloidamyloidplaque area and total plaque area and total

A

Aββ

--improvement in cognitive functionimprovement in cognitive function Immune response against

Immune response against AAββpeptidepeptide

A

Aββvaccinationvaccination

?

--Reduced risk of developing AD in patients Reduced risk of developing AD in patients treated with

treated with statinsstatins

--StatinsStatinsreduce cerebral reduce cerebral AAββload in guinea load in guinea

pigs and mice

Decrease

Decrease AAββproduction by reducing production by reducing cholesterol levels (mechanism remains

cholesterol levels (mechanism remains

unknown)

Statins

--Increase in soluble Increase in soluble AAββcould potentially harm the braincould potentially harm the brain

--Deficiency in vitamin B12 and SMONDeficiency in vitamin B12 and SMON In mouse models

In mouse modelsfor AD:for AD:

--decrease in decrease in amyloidamyloidplaque areaplaque area

--improvement in general healthimprovement in general health

Solubilization

Solubilizationof of AAββdeposits and deposits and prevention of aggregate formation by

prevention of aggregate formation by

metal

metal chelationchelation

Metal

Metal chelatorschelators

Unclear whether pharmacologically possible

In vivo

In vivo (mice) demonstration that (mice) demonstration that

Neprilysin

Neprilysinand IDE and IDE deficiency results in deficiency results in

higher

higher AAββlevels levels Increase

Increase AAββdegradation and clearancedegradation and clearance

Activators of Activators of AAββ- -degrading degrading enzymes enzymes

--Inhibition of Notch signalling could affect haematopoiesis Inhibition of Notch signalling could affect haematopoiesis

and lymphocyte differentiation

--Possible side effects associated with lack of cleavage of Possible side effects associated with lack of cleavage of

other membrane proteins

--Possible effect on nuclear signallingPossible effect on nuclear signalling

γ

γ--secretasesecretaseinhibitors decrease inhibitors decrease AAββlevels in levels in

the brain of a mouse model for AD

Decrease

Decrease AAββsynthesis synthesis γ γ--secretasesecretase inhibitors inhibitors ? ?

BACE1 knock out mice are normal

Decrease

Decrease AAββsynthesissynthesis

β

β--secretasesecretase inhibitors

inhibitors

Effects

Effectsare are onlyonlymodestmodest

Controversial

Controversialclinicalclinicaldata on data on theirtheirefficacyefficacy

Modest

Modestimprovementimprovementin cognitive in cognitive functionfunction

and

andbehaviourbehaviour

Reduce

Reduceoxidativeoxidativedamage in damage in thethebrainbrain

that

thatcontributescontributesto to neurodegenerationneurodegeneration Free

Freeradical radical scavengers

scavengersandand

antioxidants

Only

Onlypalliativepalliative

At least

At least forforsomesome, , somesomeimprovementimprovementin in

memory

memory, , concentrationconcentrationand and moodmood

Boost the

Boost the activityactivityand and probablyprobablygrowthgrowth

of neurons in

of neurons in undamagedundamagedregionsregionsof the of the brain brain Cognition Cognition enhancers enhancers Do

Do notnotaffect the affect the progressionprogressionof the of the diseasedisease Modest

Modest cognitivecognitiveand and behavioralbehavioral

improvement

improvementin AD in AD patientspatients Enhancement

Enhancementof of cholinergiccholinergictransmisiontransmision Cholinesterase Cholinesterase inhibitors inhibitors Acetylcholine Acetylcholine boosters boosters

CONs

PROs

Aim

Drug

class

Strategies for treating AD

(

www.clinicaltrials.gov

;

www.cochrane.org

)

A

n

t

i

a

m

y

l

o

i

d

(33)