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Biomedical subjects

G I De Jong

Publications and source records attributed to G I De Jong.

11 recordsLinked to original sources
PubMed2000

Pathological features of cerebral cortical capillaries are doubled in Alzheimer's disease and Parkinson's disease.

Cerebral capillaries represent a major interface between the general circulation and the central nervous system and are responsible for sufficient and selective nutrient transport to the brain. Structural damage or dysfunctioning carrier systems of such an active barrier leads to compromised nutrient trafficking. Subsequently, a decreased nutrient availability in the neural tissue may contribute to hampered neuronal metabolism, hence to behavioral and cognitive functional deficiencies. Here we focus on the ultrastructural abnormalities of cerebral microvessels in Alzheimer's disease (AD: n = 5) and Parkinson's disease (PD; n = 10). The capillary microanatomy in samples from the cingulate cortex was investigated by electron microscopy and severe damage to the vessel walls was observed. Characteristic pathological changes including capillary basement membrane thickening and collagen accumulation in the basement membrane were enhanced in both AD and PD. The incidence of capillaries with basement membrane deposits was two times higher in AD and PD than in age-matched controls. Degenerative pericytes in all groups appeared at a similar frequency. The data indicate that basement membrane deposits, as opposed to pericytic degeneration, represent an important pathological feature of AD and PD and suggest that capillary dysfunction may play a causal role in the development of these two major neurodegenerative diseases.

Aged↗
PubMed2000

Similar ultrastructural breakdown of cerebrocortical capillaries in Alzheimer's disease, Parkinson's disease, and experimental hypertension. What is the functional link?

The brain, as an intensely active organ, is highly dependent on a sufficient nutrient and oxygen availability in order to reach its optimal working capacity. It is well known that the vital supply of energy substrates is provided by the circulatory system, which splits up into a fine, terminal capillary network in target tissues. These capillaries are considered as important sites, since the actual nutrient trafficking takes place through their walls. That is why an intact, preserved structure of the microvessels is crucial to fulfill their function. Since the brain is known to be particularly vulnerable to suboptimal oxygen and glucose delivery, the intact morphology of capillaries is of paramount importance. Several observations have indicated that the cerebral capillary ultrastructure is damaged in Alzheimer's disease (AD). Curiously, the regional cerebral blood flow of AD patients is also significantly lower than in age-matched control individuals. Based on these data, it has been suggested that the decreased blood supply and the cerebrovascular alterations contribute to the development of dementia. However, we have observed similar capillary damage in Parkinson's disease patients and chronically hypertensive rats in addition to AD cases, as presented here. These findings indicate that cerebral capillary damage is not exclusive for AD but occurs under other neurodegenerative disorders and hypertension, as well. We hypothesize that ultrastructural abnormalities of cerebral capillaries are causally related to decreased cerebral blood flow and create a condition that favors neurodegenerative mechanisms including the development of dementia.

Alzheimer Disease↗
PubMed1999

Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment.

The impact of chronic cerebral hypoperfusion on cognitive function and cerebral capillary morphology in the hippocampus was examined. Young adult Wistar rats were subjected to permanent ligation of both common carotid arteries (two-vessel occlusion). One month after vascular occlusion, a small but non-significant impairment in the acquisition of spatial information was registered compared with sham-operated controls. Two months after surgery, the occluded animals displayed an impaired performance throughout the training period. One year after surgery, the acquisition curves demonstrated a significant attenuation of the learning rate in the occluded rats group, whereas no significant differences in long-term retention were observed. Thus, chronic hypoperfusion induced by two-vessel occlusion gave rise to impairment of spatial memory. Following behavioural testing, the rats were killed at the age of 17 months, and capillaries in the CA1 and dentate gyrus were examined using transmission electron microscopy. Typical age-related capillary abnormalities such as degenerative pericytes and thickened basement membranes (with or without fibrosis) were detected in the hippocampus of sham animals. In occluded rats, the occurrence of capillaries displaying such abnormalities almost doubled in the CA1 region, but was similar in the dentate gyrus, compared with sham controls. A highly significant correlation was found between the last Morris maze performance and the percentage of capillaries with deposits in the basement membrane in the hippocampal CA1 area of occluded rats, which was not present in the sham animals. We conclude that a long-term hypoperfusion accelerated the development of age-related ultrastructural aberrations of capillaries in the hippocampal CA1 area, but not in the dentate gyrus. Thus, not only neurons, but also capillaries in the hippocampal CA1 area are sensitive to an impaired microcirculation. Moreover, the cognitive performance of hypoperfused rats correlated closely with the condition of the capillaries in the CA1 area, suggesting that capillary integrity is one of the important determinants of brain function in conditions that compromise cerebral microcirculation.

Animals↗
PubMed1998

Beta-amyloid-induced cholinergic denervation correlates with enhanced nitric oxide synthase activity in rat cerebral cortex: reversal by NMDA receptor blockade.

Ample experimental evidence indicates that acute beta-amyloid infusion into the nucleus basalis of rats elicits abrupt degeneration of the magnocellular cholinergic neurons projecting to the cerebral cortex. In fact, involvement of a permanent Ca2+ overload, partially via N-methyl-D-aspartate (NMDA) receptors, was proposed as a pivotal mechanism in beta-amyloid-induced neurodegeneration. A definite measure of NMDA receptor-mediated processes and subsequent Ca2+ entry is the induction of Ca2+/calmodulin-activated neuronal nitric oxide synthase (nNOS) in nerve cells. In the present account we therefore assessed activation of nNOS in correlation with cholinergic decline after beta-amyloid(1-42) or beta-amyloid(25-35) infusion into the rat nucleus basalis. The results demonstrate the beta-amyloid conformation-dependent enhancement of cortical nitric oxide synthase (NOS) activity. Furthermore, chronic application of the polyamine site NMDA receptor blocker ifenprodil effectively attenuated beta-amyloid neurotoxicity. We propose that nNOS activation reflects the degree of beta-amyloid-induced excitotoxic injury in a proportional manner. Moreover, Ca2+-mediated processes via NMDA receptors, or direct binding of beta-amyloid to this receptor may be a critical step in the neurotoxic mechanisms in vivo.

Amyloid beta-Peptides↗
PubMed1997

Cerebrovascular hypoperfusion: a risk factor for Alzheimer's disease? Animal model and postmortem human studies.

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.

Aging↗
PubMed1995

Beta-amyloid (1-42) affects cholinergic but not parvalbumin-containing neurons in the septal complex of the rat.

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).

Amyloid beta-Peptides↗
PubMed1995

Nimodipine prevents early loss of hippocampal CA1 parvalbumin immunoreactivity after focal cerebral ischemia in the rat.

The effect of focal cerebral ischemia induced by middle cerebral artery occlusion on hippocampal interneurons containing the calcium-binding protein parvalbumin (PV) was studied in rats. Four hours after the onset of ischemia, a reduced number of PV-immunoreactive (-ir) neurons was observed in the lateral part of the CA1 region, while PV-ir was not altered in the CA2 and CA3 areas. Pretreatment with the L-type Ca2+ channel blocker nimodipine prevented the ischemia-induced loss of PV-ir in the CA1, suggesting a role for L-type voltage sensitive calcium channels in the mechanism of early neuronal alterations in the hippocampus CA1 region after focal cerebral ischemia.

Animals↗
PubMed1993

Muscarinic acetylcholine receptor-expression in astrocytes in the cortex of young and aged rats.

The present report describes the cellular and subcellular distribution pattern of immunoreactivity to M35, a monoclonal antibody raised against purified muscarinic acetylcholine receptor protein, in astrocytes in the cerebral cortex of young and aged rats. Most M35-positive astrocytes were localized in the superficial layers of the cortex and part of the corpus callosum. At the ultrastructural level, immunoprecipitates were localized in the Golgi complexes, but the nucleus, rough endoplasmic reticulum, mitochondria, and microfilaments were generally free of labeling. Labeling was also present associated to the cell membrane, although without the characteristic immunoreactive postsynaptic membrane thickening found in neuronal structures. In aging rats of 30-34 months, the number of M35-labeled astrocytes doubled, whereas the neuronal staining slightly decreased in the same region in half of the animals studied. Fluorescent double-labeling for M35 and GFAP, an astrocytic microfilament protein, revealed that all M35-positive glial cells express GFAP and, conversely, that almost all GFAP glial cells were M35-immunostained. Based on the high incidence of coexpression of mAChRs and GFAP, both proteins may be functionally linked to each other. Rough semiquantitative estimates revealed that in young adult rats the GFAP/M35-immunoreactive astrocytes made up approximately one fifth of all cortical astrocytes. An important aspect of the presently demonstrated immunoreactivity of astroglia to mAChR proteins is its labeling in situ instead of in tissue culture. This finding may further support investigation, e.g., on anatomical relations of astroglia with neuronal and vascular elements, and its reactivity in experimental conditions.

Aging↗
PubMed1993

Reversed alterations of hippocampal parvalbumin and protein kinase C-gamma immunoreactivity after stroke in spontaneously hypertensive stroke-prone rats.

BACKGROUND AND PURPOSE: Aging spontaneously hypertensive stroke-prone rats (SHR-SP) were previously shown to develop neocortical strokes. Because the hippocampal CA1 is selectively vulnerable to abnormal brain perfusion, the neuropathological effects of spontaneous strokes were investigated on specific neurochemical alterations in two major cell types of the hippocampal CA1 in SHR-SP. METHODS: The immunoreactivity for the gamma-isoform of protein kinase C (in pyramidal cells) and parvalbumin (in interneurons) was determined in the hippocampal CA1 by applying monoclonal antibodies. Because chronic treatment with the calcium antagonist nimodipine prevents the development of strokes in SHR-SP, we compared SHR-SP (stroke) with age-matched nimodipine-treated rats (nonstroke). RESULTS: After stroke in control animals, we observed a strikingly enhanced immunoreactivity for protein kinase C-gamma in CA1 pyramidal cells compared with nimodipine-treated rats, which can be interpreted as the result of an increased activation of these cells. The pathological increase of protein kinase C-gamma immunoreactivity was accompanied by a reduced parvalbuminergic innervation of these pyramidal cells in symptomatic SHR-SP. CONCLUSIONS: Because parvalbumin is present in a subset of GABAergic inhibitory interneurons, these data suggest that increased activity of CA1 pyramidal cells after spontaneous stroke may partially be related to a decreased inhibitory input on these cells.

Aging↗
PubMedDate not supplied

Calcium antagonists decrease capillary wall damage in aging hypertensive rat brain.

Chronic hypertension during aging is a serious threat to the cerebral vasculature. The larger brain arteries can react to hypertension with an abnormal wall thickening, a loss of elasticity and a narrowed lumen. However, little is known about the hypertension-induced alterations of cerebral capillaries. The present study describes ultrastructural alterations of the cerebrocortical capillary wall, such as thickening and collagen accumulation in the basement membrane of aging spontaneously hypertensive stroke-prone rats. The ratio of cortical capillaries with such vascular pathology occurred significantly more frequently in hypertensive animals. Nimodipine and nifedipine are potential drugs to decrease blood pressure in hypertension but their beneficial effects in experimental studies reach beyond the control of blood pressure. Nimodipine and nifedipine can alleviate ischemia-related symptoms and improve cognition. These drugs differ in that nifedipine, but not nimodipine reduces blood pressure at the here-used concentration while both drugs can penetrate the blood-brain barrier. Here we show that chronic treatment of aging hypertensive stroke-prone rats with nimodipine or nifedipine could preserve microvascular integrity in the cerebral cortex.

Aging↗