ACH: Involvement in diseases

Myasthenia gravis

Symptoms: loss muscular tonus progression from head to limbs to respiratory muscles

Curare produces a similar effect

Muscle sum-potentials

Therapy

Thymectomy

ACH-Esterase-inhibitors

Suppression of immune response

Plasma exchange

Alzheimer‘s disease

Alois Alzheimer: Marktbreit 1864 – 1915 1906: reports in Tübingen about the disease The term designates dementia appearing before the age of 65After 65: senile dementia of the Alzheimer‘s type

Frequency/Prevalence

4 million americans suffer from AD1,6 million germans

US society spends about 100 $ billions/yearUS bussiness loses about 61 $ billions/year

Famous Alzheimer‘s disease patients

Immanuel Kant

Herbert Wehner

Ronald Regan

Margaret Thatcher

Auguste D.First diagnosed patient

Symptoms

Progressively: 1. Loss of short term memory (declarative memory, procedural memory is spared)2. Orientation deficits (allocentric orientation)3. Personality changes4. Depression5. Loss of all cognitve abilites

Alzheimer‘s Disease as a Chronic Disease

Protective factors: Education / ? Occupation

Malignant Phase

Neuritic plaques, tangles, neuron and synapse loss

Initiationfactors:

Trisomy 21

Mutations: APP Presenilin-1 Presenilin-2

SusceptibilityAlleles: APO EE4 ? Bleomycin hydrolase ?? LRP

Promotingfactors:

Age Head trauma

Diffuseplaques

LatentPre-clinical

PhaseClinical

symptomsappear

Diagnosis

Losesindependence

Death

Neuropharmacology Uni-Tuebingen

Pathophysiology of AD

Plaques:Amyloid precursor Protein (APP) cleavage

by alpha secretase : non amyloidogenic

by beta or gamma secretase: amyloidogenic,forms Amyloid-beta-protein (Aß)consitsting of 40 to 42 amino acids.

Aggregation of Aß and formation of extracellular Plaques.

Processing of APP to amyloid=ßA4

Non amyloidogenicamyloidogenic

beta secretase Alpha ßA4secretase gamma secretase

APP

Tangles: Intracellularly aggregating paired helical filaments (diam 10 nm, length > 200 nm) consisting of insoluble phosphorylated proteins, mainly tau-protein.

GliosisInflammatory processes followed by gliosis

Preferentially affected brain structures Initial stage:Tangles in the entorhinal cortexPlaques in the HippocampusDegeneration of the tractus perforans

loss of giant ACH cells in the NBM

Advanced stage:Tangles and plaques throughout the cortex

Degeneration in the NBM

Preferentially affected neurotransmitter systems

Dramatically reduced: CAT / ACH synthesis ACH-Esterase Choline transporter GLU-activity Moderately reduced: Noradrenaline-activity Dopamine-activity Serotonine-activity some peptides

Unchanged: GABA free amino acids most peptides

Hypothesis 1

The cause of Alzheimer‘s is the beta A4 plaque

Hypothesis 2

The cause of Alzheimer‘s is tangle foramtion

Hypothesis 3

The cause of Alzheimer‘s is unknown

Hypothesis 3 Alzheimer‘s disease

Unknowncause

Genetic< 10 %

TanglesCell deathin EC-hippocampusNBM

Expression of APPas a spill over of a repair mechanism

amyloidosis

Plaques

Neuropharmacology Uni-Tuebingen

Therapy

Neuroprotective Therapy: not available

Research focus: Inhibition of APP expression Inhibition of β or γ secretase Immunisation NSAIDS (Ibuprofen, Indomethacine) Glutamate antagonism

Substitution therapy: enhancing ACH activity

Research focus: inhibiting inactivation of second messengers MEM1414: Phosphodiesterase-Inhib. (blocks break-down of c-AMP)

Substitution therapy:

enhancing ACH activity with:

ACH-Esterase inhibitors: Tacrine Donepezil Rivastigmine Metrifonate Galantamine

Muscarinic receptor-agonists: under development

Nicotininc receptor-agonits: under development

Unknown mechanism: Propentofylline

Glutamate antagonism: Memantine (Axura)

Behavioural Pharmacology

Modeling AD

Modeling amyloidosis with transgenic animals

Modeling tangle formation: not accomplished (???)

Modeling reduced ACH activity (with anti-ACHergics)

Modeling degeneration of NBM cells (with 192 IgG-saporin)

Modeling reduced glutamate-activity

Modeling degeneration of the perforant pathway/hippocampus

Behavioural tests:

Learning tests: Time course:Acquisition – consolidation – storage – retrieval

Types of learning: declarative non-declarative / procedural

Preferentially affected in AD:

Declarative learning (= acquisition of declarative memory)

A rodent model for declarative learning

Allocentric orientation in a maze- Morris water maze- 8-arm radial mazeOrientation according to extra-maze cues (landmarks)Requires hippocampal functions intact hippocampal Glu-System intact ACH systemA rodent model for ADExperimentally induced dysfunction results inLearning deficits, Short term memory deficits

Learning and memory tests

Passive avoidanceActive avoidanceInstrumental conditioningSocial recognitionObject recognitionMatching to sampleMatching to place = Maze tasks

Animal models of Alzheimer‘s diseaseAnimal models of Alzheimer‘s disease

Induction of a model-dementiaActeylcholine-Antagonists (Scopolamine) Lesion of the N.basalis magnocellularis

Glutamate/NMDA-Receptor-Antagonists lesion of the hippocampus

Transgenic mice

Testing learningMazes: Water, 8-armMatching to sample tasks