Hyperhomocysteinemia and vascular dementia

Alzheimers disease and vascular dementia are the two most common disorders for elderly people over 65 years. Recent evidence suggests that Alzheimers disease and vascular dementia share common risk factors and may originate from cerebrovascular damage. The aim of this project is to develop an in vivo rat model for vascular dementia and to investigate mechanistic effects in different in vitro models, the brain capillary endothelial cells, the blood-brain barrier and organotypic brain slices. We will use hyperhomocysteinemia, which has been shown to damage the cerebrovascular system and to induce cognitive impairment. Homocysteine is an amino acid, important in the metabolism of cells and (1) it exerts direct neurotoxic properties, (2) damages the cerebrovascular system and (3) induces metabolic dysfunctions. Four subprojects will be performed by two MD/PhD students. Student 1 will perform in vivo studies and will investigate (1) the effects of hyperhomocysteinemia on the cholinergic neurons of the basal nucleus of Meynert, (2) the damage of the cerebrovascular system and (3) the impairment of cognition and subsequent hypothetical conversion into Alzheimer-like pathology. Student 2 will perform in vitro studies and will investigate (1) the effects of hyperhomocysteinemia on cholinergic neurons in brain slices, (2) the damage on brain capillaries and the blood-brain barrier and (3) modulatory effects of inflammation, oxidative stress and glutamate-mediated toxicity. In summary, this project (1) should bring new insights into the mechanism of hyperhomocysteinemia, (2) should characterize a physiological in vivo rat model for vascular dementia and (3) should study possible conversion into Alzheimer-like pathology. Such a model may allow to study biochemical parameters for subsequent diagnosis of vascular dementia in humans in future.

Alzheimer`s disease (AD) is a severe chronic neurodegenerative disorder of the brain, characterized by aggregations of a small peptide (beta-amyloid), neuronal inclusions (tau tangles), inflammation in the brain, cell death, mainly of the neurotransmitter acetylcholine and damage of the cerebrovascular system. The reasons for developing AD are unknown, but the major risk factor is age (>60 years), since less than 2.5% of AD is genetically determined. Epidemiological studies show that specific risk factors support development of AD: atherosclerosis, diabetes, homocysteine, hypertension or cholesterol, all risk factors which are also vascular risk factors. Thus we aim to ask: is AD a vascular disease? In the present project we study if rats, treated for long-term (5 or 15 months) with homocysteine (hyperhomocysteinemia) or cholesterol (hypercholesterolemia) develop an AD-like pathology. Our experiments show that homocysteine-treatment for short time (5 months) declines cognition and reduces the activity of the cholinergic neurons, while rats treated for 15 months with homocysteine partly counteract this decline, but still have a marked decline in cognition. On the other hand, rats treated for 5 months with high choesterol exhibit a markedly reduced cognitive learning, dramatically enhanced inflammation in the brain and a decline of the cholinergic neurons. It was interesting to note that both disease models exhibited marked microbleedings in the brain. Our data show that hypercholesterolemia displayed an "Alzheimer-like pathology". Both models showed microbleedings in the brain, indicating that severe small lesions of the brain capillaries over decades may contribute to the development of AD. It seems possible that a damage of the vascular system over decades may induce dementia in high age. We are now interested in further studies to combine cholesterol with homocysteine and also with ethanol, to observe a possible potentiation of the effect. Therapeutically this could mean, that an improvement of life style (blood pressure, food, exercise) may markedly improve memory and may delay the development of dementia in humans.