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Transcript of ACH: Involvement in diseases Myasthenia gravis Symptoms: loss muscular tonus progression from head...
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ACH: Involvement in diseases
Myasthenia gravis
Symptoms: loss muscular tonus progression from head to limbs to respiratory muscles
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Curare produces a similar effect
Muscle sum-potentials
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Therapy
Thymectomy
ACH-Esterase-inhibitors
Suppression of immune response
Plasma exchange
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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
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Famous Alzheimer‘s disease patients
Immanuel Kant
Herbert Wehner
Ronald Regan
Margaret Thatcher
Auguste D.First diagnosed patient
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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
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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
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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.
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Processing of APP to amyloid=ßA4
Non amyloidogenicamyloidogenic
beta secretase Alpha ßA4secretase gamma secretase
APP
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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
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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
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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
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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
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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
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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)
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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)
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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
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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)
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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
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Learning and memory tests
Passive avoidanceActive avoidanceInstrumental conditioningSocial recognitionObject recognitionMatching to sampleMatching to place = Maze tasks
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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