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 – : reports in Tübingen about the disease The term designates dementia appearing before the age of 65 After 65: senile dementia of the Alzheimer‘s type Frequency/Prevalence 4 million americans suffer from AD 1,6 million germans US society spends about 100 $ billions/year US 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 changes 4.Depression 5.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 Initiation factors: Trisomy 21 Mutations: APP Presenilin-1 Presenilin-2 Susceptibility Alleles: APO E E 4 ? Bleomycin hydrolase ?? LRP Promoting factors: Age Head trauma Diffuse plaques Latent Pre-clinical Phase Clinical symptoms appear Diagnosis Loses independence Death N europharmacology 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 amyloidogenic amyloidogenic beta secretase Alpha ßA4 secretase gamma secretase APP

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

Preferentially affected brain structures Initial stage: Tangles in the entorhinal cortex Plaques in the Hippocampus Degeneration 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 Unknown cause Genetic < 10 % Tangles Cell death in EC-hippocampus NBM Expression of APP as a spill over of a repair mechanism amyloidosis Plaques N europharmacology 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 maze Orientation according to extra-maze cues (landmarks) Requires hippocampal functions intact hippocampal Glu-System intact ACH system A rodent model for AD Experimentally induced dysfunction results in Learning deficits, Short term memory deficits

Learning and memory tests Passive avoidance Active avoidance Instrumental conditioning Social recognition Object recognition Matching to sample Matching to place = Maze tasks

Animal models of Alzheimer‘s disease Induction of a model-dementia Acteylcholine-Antagonists (Scopolamine) Lesion of the N.basalis magnocellularis Glutamate/NMDA-Receptor-Antagonists lesion of the hippocampus Transgenic mice Testing learning Mazes: Water, 8-arm Matching to sample tasks