Dementia (including Alzheimer's disease) (AD) is the fourth most important cause of death in the developed world. Alzheimer's disease is characterized by cognitive impairment and profound behavioural changes leading to death after several years of progressive illness. At the neurochemical level, AD is characterized by a considerable loss of cholinergic neurons leading to a decrease of acetylcholine concentration in the temporal cortex and the cerebrospinal fluid. Other neurotransmitter systems (monoamines, neuropeptides, excitatory and inhibitory amino acids) also exhibit abnormalities. A conclusive diagnosis is only possible after post-mortem brain examination revealing senile plaques, neurofibrillary tangles, dystrophic neurites and neuronal cell loss in specific regions of the brain. Because of the growing group of elderly in our society, AD is a continuously growing medical and socio-economical problem. Unfortunately the exact ethiology of AD still remains unknown. The major goal of AD research is to produce animal models that exhibit pathologic and/or phenotypic features of the humans affected by the disease to learn more about its pathophysiology and to create new treatment opportunities. Mutations in different genes are thought to be related to an increased risk of developping AD. It is one of our goals to validate a mouse model that expresses a mutated 751-amino acid isoform of hAPP under the control of the neuron-specific enolase promotor of the rat. A base substitution on chromosome 21 causes a missense mutation (Val717 ? Ile717) that can be found in patients with familial AD. Behavioural testing examines possible cognitive impairment in an animal model to search for similarities between the deficits in the animals and the cognitive impairment in the human condition. Behavioural testing will be performed on 3, 6 and 12 month old mice. The model expresses low levels of hAPP and does not develop ?-amyloid deposits, and therefore it might be possible to provoke these pathological features. Recent literature states a possible connection between cholesterol, the deposition of A?, and AD. A chronic provocation will be established by putting the mice on a high fat diet (constitution: 15% cacaobutter, 0.5% cholate, 1% cholesterol, 40.5% sucrose, 10% cornstarch, 1% corn oil, and 4.7% cellulose) during 24 weeks. Head injuries cause brain damage leading to physical, cognitive, and behavioural disturbances in humans. In order to further examine this hypothesis a traumatic model of closed head injury for mice will be developed. The effects of these two provocations will be examined at the level of behaviour and cognition, and histopathological examinations will be performed as well. An important motive to generate transgenic (mouse) models is the possibility to test new therapeutic strategies. Prophylactic drugs and drugs used in the symptomatic treatment of human AD patients will be administered to the animals. Whether these drugs can prevent or diminish cognitive deficits should show up during behavioural testing following or during treatment. Since no earlier neurochemical research has been performed, the concentration of neurotransmitters in the brain of the NSE-hAPP751m-model is not known. If behavioural testing of the models reveals cognitive deficits, neurochemical testing will be carried out. Determinations will be performed electrochemically on homogenates of brain tissue after separation of substances by high pressure liquid chromatography (HPLC). The different sections of the research proposal should make it possible for us to validate the different mouse models, and if this turns out possitive these new models could be used for the testing of new pharmaceuticals.