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Although cognitive impairment during aging is usually associated with neuronal alterations, the cerebrovascular system undergoes prominent alterations in aging as well. Using electron microscopy we previously showed a progressive deterioration of the capillary wall in the cerebral cortex of aged rats. In aged rats the capillary basement membrane (BM) is thickened, massive bundles of collagen fibrils are deposited within the BM, and pericytes are degenerating. A compromized cerebral circulation (e.g., in rats with chronic hypertension) is characterized by an increased number of capillary alterations. In autopsy material (gray matter, gyrus cinguli) of carefully diagnosed patient groups (controls, AD, Lewy body disease, MID and demented Lewy body disease patients) we observed significantly more morphological changes in the capillary bed of demented versus non-demented patients. In both animal and human material morphological evidence points to a relation between energy-dependent nutrient transport across the blood-brain barrier and the ultrastructural deviations. In the AD cases we did not find a correlation between the stage of the disease (Braak I-VI) and the incidence of capillary aberrations, which indicates that the capillary alterations are not a consequence of AD pathology. Simultaneously, we are conducting animal model studies to determine the effects of cerebral hypoperfusion in the rat. Permanent bilateral occlusion of the carotid arteries shifts the behavioral profile of the rats (Morris maze, open field) towards that of aged rats, while the sensitivity for muscarinic ligand agents is altered.

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beta-Amyloid(1-42) peptide (beta AP(1-42) was injected into the medial septum of rats. After a 14-day survival time, neuronal alterations in the septal cholinergic and GABAergic systems were visualized by means of histo- and immunocytochemical methods. Neurons insulted by the peptide were primary choline acetyltransferase-immunoreactive (ir), while only minor effects of beta AP(1-42) were observed on parvalbumin-ir interneurons. These results indicate that the changes in intracellular Ca2+ level elicited by beta AP(1-42) may contribute to beta-amyloid neurotoxicity, and Ca(2+)-binding proteins may play an important role in the protection against the neurotoxic effects of beta AP(1-42).