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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