Lessen voor de 21 ste eeuw Bart De Strooper

(1)

KULeuven

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) 6. Discussie

(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

delirium, wanen, depressie, gedragsstoornissen

Normale veroudering en milde cognitieve storing

(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 FTD

Jacob Creutzfeld en prion ziekten Aids

(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 A_1-42 A1-42 A1-42 A1-42 A1-42 A1-42 A1-40 A1-40 Amyloide plaque

(13)

A_1-42 A_1-42 A_1-42 A_1-42 A_1-42 A_1-42 A1-40 A1-40 A1-42 KM DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK 40 * * * * * 1 (Edmann degradatie)

Glenner and Wong, 1984

Kang et al, 1987 -Amyloid peptide Precursor Protein

(14)

De APPtisten versus de TAUoisten

(15)

Vragen Aggregates A1-42 A1-42 A1-42 A1-42 A_1-42 A1-42 A_1-40 A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 early early opmerkingen Down’s syndrome Risk factor 0.05% of all AD

(17)

KM DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK KM NL 1 11  _* 40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 670 693 709 Bace2 724 ₄₉ Swed ish

-secretase _{-secretase} _{-secretase}

Austr ian Fren ch FloridaLond on Austr alian Flem ish Dutch -Itali an-A rctic V T I

(18)

The amyloid cascade hypothesis voor de ziekte van Alzheimer

A

APP

Swedish, Flemish

London, French, Florida Austrian

Presenilins Protofibrils ?

A_1-40

A_1-40 AA1-42_1-42

Aggregates ? A1-42 A1-42 A1-42 A1-42 A1-42 A1-42 A1-40 A_1-40

(19)

-Amyloid peptide Precursor Protein =APP

1. A 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

Geen verklaring voor neuronale dysfunctie

Argumenten voor de amyloid hypothese

(20)

N

C

The presenilins in Alzheimer’s Disease A 

K M T V I V I T L V M L 1 1 6 4 0 4 2 D A E F R H D S G Y E V H H Q K L V F F A E D V G S N K G A I I G L M V G G V V I A 4 9 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

A inbrengen in hersenen? Proeftherapie?

(22)

Proefdiermodel

-COOH

APP695 A

Thy-1 promotor polyA signal

A4 A4 A4 A4 A4 A4 A4 A4

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)

recorded from CA1

potentiation of responses 20 min after HFS

(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 L A TE N C Y (i n s) 0 50 100 150 200 250 300 350 400 % T IM E IN Q U AD RA 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 ? A APP ? Protofibrils A_1-40 A_1-40 A1-42 A1-42 A1-42 A1-42 A_1-42 A1-42 A1-42 A1-42 A1-40

Tangles and cell death

Aggregates ? Aggregates ? A APP _A APP ? Protofibrils A_1-40 A_1-40 ? Protofibrils A_1-40 A_1-40 Protofibrils A_1-40 A_1-40 A1-42 A1-42 A1-42 A1-42 A1-42 A1-42 A_1-42 A1-42 A1-42 A1-42 A1-40 A1-42 A1-40

Tangles and cell death Tangles and cell death Production

Secretase-inhibitors

Vaccination

Toxicity Inflammation

Neuronal dysfunction (cholinesterase inhibitors)

Clearance ?

(27)

Hong et al., Science 2000

Beta-secretase

SPPro DTGS DTGS

(28)

Het -secretase complex N C Asp₂₅₇ Asp385 Presenilin Nicastrin N APH1 PEN-2 PS1+/-PS2-/- PS1-/- PS2-/- PS1+/-PS2-/- PS1-/- precursor cel NOTCH

(29)

N O T C H S 1 S 2 S 3 APP  

Presenilin

ADAM

Regulated Intramembrane Proteolysis (RIP)

precursor cel

NOTCH

A AICD

(30)

Dale Schenk, Nature 1999 A

A A

(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 NSAIDs

-Specific inhibition of Specific inhibition of AA1-421-42 generation generation

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

contributes to neuronal loss

-Inhibition of A

-Inhibition of A1-421-42 generation generation NSAIDs

NSAIDs

-Risk of autoimmunity and brain inflammation

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

as they do in mice

-immune response might not be efficient in older people

-immune response might not be efficient in older people In mouse models for AD:

In mouse models for AD:

-decrease in amyloid plaque area and total

A

A

-improvement in cognitive function

Immune response against A

Immune response against A peptide peptide A

A vaccination vaccination

?

? -Reduced risk of developing AD in patients

-Reduced risk of developing AD in patients

treated with statins

-Statins reduce cerebral A

-Statins reduce cerebral A load in guinea load in guinea pigs and mice

pigs and mice Decrease A

Decrease A production by reducing production by reducing cholesterol levels (mechanism remains

cholesterol levels (mechanism remains

unknown)

Statins

-Increase in soluble A

-Increase in soluble A could potentially harm the brain could potentially harm the brain -Deficiency in vitamin B12 and SMON

-Deficiency in vitamin B12 and SMON In mouse models for AD:

In mouse models for AD:

-decrease in amyloid plaque area

-improvement in general health

-improvement in general health Solubilization of A

Solubilization of Adeposits and deposits and prevention of aggregate formation by

prevention of aggregate formation by

metal chelation

Metal chelators

Unclear whether pharmacologically possible

In vivo

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

Neprilysin

Neprilysin and IDE and IDE deficiency results in deficiency results in higher A

higher Alevels levels Increase A

Increase Adegradation and clearancedegradation and clearance Activators of A Activators of A- -degrading degrading enzymes enzymes

-Inhibition of Notch signalling could affect haematopoiesis and

lymphocyte differentiation

-Possible side effects associated with lack of cleavage of

other membrane proteins

- Possible effect on nuclear signalling

- Possible effect on nuclear signalling 

-secretase inhibitors decrease A-secretase inhibitors decrease A levels in levels in the brain of a mouse model for AD

the brain of a mouse model for AD

Decrease ADecrease Asynthesis synthesis -secretase -secretase inhibitors inhibitors ? ?

BACE1 knock out mice are normal

Decrease A

Decrease Asynthesissynthesis



-secretase -secretase inhibitors

inhibitors

Effects are only modest

Controversial clinical data on their efficacy

Modest improvement in cognitive function

and behaviour

Reduce oxidative damage in the brain

that contributes to neurodegeneration

Free radical Free radical scavengers and scavengers and antioxidants antioxidants Only palliative Only palliative

At least for some, some improvement in

memory, concentration and mood

memory, concentration and mood Boost the activity and probably growth

Boost the activity and probably growth

of neurons in undamaged regions of the

brain brain Cognition Cognition enhancers enhancers

Do not affect the progression of the disease

Modest cognitive and behavioral

improvement in AD patients

Enhancement of cholinergic transmision

Enhancement of cholinergic transmision Cholinesterase Cholinesterase inhibitors inhibitors Acetylcholine Acetylcholine boosters boosters CONs CONs PROsPROs Aim Aim Drug Drug class class

Strategies for treating AD (www.clinicaltrials.gov; www.cochrane.org)

A n t i a m y l o i d

(33)

1970 ₁₉₉₀ 1995 1999 -secr etase pres enili n -sec reta se 2002 Acety lcholi ne-h ypot hese Acety lcholi ne-h ypot hese ther apie TIJD….