Biomedical subjects

P G Luiten

Publications and source records attributed to P G Luiten.

At least 19 recordsLinked to original sources

PubMed2001

Cortical cholinergic decline parallels the progression of Borna virus encephalitis.

Borna disease virus (BDV)-induced meningoencephalitis is associated with the dysfunction of the cholinergic system. Temporal development of this cholinergic decline during pre-encephalitic and encephalitic stages of BDV infection remains however elusive. Changes in choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities were therefore determined in the cerebral cortex, hippocampus, striatum, amygdala and cholinergic basal forebrain nuclei (ChBFN) of rats infected with BDV. Immunocytochemistry for ChAT and vesicular acetylcholine transporter (VAChT) was employed to identify morphological consequences of BDV infection on cholinergic neurons. Whereas both ChAT and AChE activities changed only slightly under pre-encephalitic conditions, the encephalitic stage was characterized by a significant decrease of ChAT activity in the cerebral cortex, horizontal diagonal band of Broca (hDBB), hippocampus and amygdala concomitant with a marked reduction of AChE activity in the cerebral cortex, hDBB and hippocampus. The striatum and medial septum remained unaffected. ChAT and VAChT immunocytochemistry revealed prominent axonal degeneration in affected cortical and limbic projection areas of ChBFN. In summary, our data indicate progressive deterioration of forebrain cholinergic systems that parallels the progression of BDV encephalitis.

Acetylcholine↗

PubMed2001

High-voltage-activated Ca2+ currents and the excitability of pyramidal neurons in the hippocampal CA3 subfield in rats depend on corticosterone and time of day.

This study tested the time-of-day dependence of the intrinsic postsynaptic properties of hippocampal CA3 pyramidal neurons. High-voltage-activated Ca2+ currents and the Ca(2+)- and voltage-dependent afterhyperpolarizations were examined in slices of rat brains obtained at four distinct time periods. Just after onset of the dark phase, the steady-state amplitude of the Ca2+ current (-1.24+/-0.11 nA) was significantly greater (P<0.03) than that of the light phase (-0.84+/-0.06 nA). Over the entire time range, the amplitude of the Ca2+ current correlated with plasma corticosterone levels in a U-shaped function. Furthermore, depolarization-induced excitability during the dark phase exhibited an increased spike after depolarization (3.1+/-0.1 mV) and a slower adaptation of the firing frequency (146+/-18%). These findings point to a dynamic time-of-day dependence of the CA3 neuronal properties and postsynaptic Ca2+ currents.

Action Potentials↗

PubMed2001

Beta-amyloid(1-42)-induced cholinergic lesions in rat nucleus basalis bidirectionally modulate serotonergic innervation of the basal forebrain and cerebral cortex.

Ample experimental evidence suggests that beta-amyloid (A beta), when injected into the rat magnocellular nucleus basalis (MBN), impels excitotoxic injury of cholinergic projection neurons. Whereas learning and memory dysfunction is a hallmark of A beta-induced cholinergic deficits, anxiety, or hypoactivity under novel conditions cannot be attributed to the loss of cholinergic MBN neurons. As mood-related behavioral parameters are primarily influenced by the central serotonergic system, in the present study we investigated whether A beta(1-42) toxicity in the rat MBN leads to an altered serotonergic innervation pattern in the rat basal forebrain and cerebral cortex 7 days postsurgery. A beta infusion into the MBN elicited significant anxiety in the elevated plus maze. A beta toxicity on cholinergic MBN neurons, expressed as the loss of acetylcholinesterase-positive cortical projections, was accompanied by sprouting of serotonergic projection fibers in the MBN. In contrast, the loss of serotonin-positive fiber projections, decreased concentrations of both serotonin and 5-hydroxyindoleacetic acid, and decline of cortical 5-HT(1A) receptor binding sites indicated reduced serotonergic activity in the somatosensory cortex. In conclusion, the A beta-induced primary cholinergic deficit in the MBN and subsequent cortical cholinergic denervation bidirectionally modulate serotonergic parameters in the rat basal forebrain and cerebral cortex. We assume that enhanced serotonin immunoreactivity in the damaged MBN indicates intrinsic processes facilitating neuronal recovery and cellular repair mechanisms, while diminished cortical serotonergic activity correlates with the loss of the subcortical cholinergic input, thereby maintaining the balance of neurotransmitter concentrations in the cerebral cortex.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2001

Cerebral microvascular pathology in aging and Alzheimer's disease.

The aging of the central nervous system and the development of incapacitating neurological diseases like Alzheimer's disease (AD) are generally associated with a wide range of histological and pathophysiological changes eventually leading to a compromised cognitive status. Although the diverse triggers of the neurodegenerative processes and their interactions are still the topic of extensive debate, the possible contribution of cerebrovascular deficiencies has been vigorously promoted in recent years. Various forms of cerebrovascular insufficiency such as reduced blood supply to the brain or disrupted microvascular integrity in cortical regions may occupy an initiating or intermediate position in the chain of events ending with cognitive failure. When, for example, vasoconstriction takes over a dominating role in the cerebral vessels, the perfusion rate of the brain can considerably decrease causing directly or through structural vascular damage a drop in cerebral glucose utilization. Consequently, cerebral metabolism can suffer a setback leading to neuronal damage and a concomitant suboptimal cognitive capacity. The present review focuses on the microvascular aspects of neurodegenerative processes in aging and AD with special attention to cerebral blood flow, neural metabolic changes and the abnormalities in microvascular ultrastructure. In this context, a few of the specific triggers leading to the prominent cerebrovascular pathology, as well as the potential neurological outcome of the compromised cerebral microvascular system are also going to be touched upon to a certain extent, without aiming at total comprehensiveness. Finally, a set of animal models are going to be presented that are frequently used to uncover the functional relationship between cerebrovascular factors and the damage to neural networks.

Aging↗

PubMed2001

Short-term consequences of N-methyl-D-aspartate excitotoxicity in rat magnocellular nucleus basalis: effects on in vivo labelling of cholinergic neurons.

Cholinergic neurons of the basal forebrain form one of the neuron populations that are susceptible to excitotoxic injury. Whereas neuropharmacological studies have aimed at rescuing cholinergic neurons from acute excitotoxic attacks, the short-term temporal profile of excitotoxic damage to cholinergic nerve cells remains largely elusive. The effects of N-methyl-D-aspartate (NMDA) infusion on cytochemical markers of cholinergic neurons in rat magnocellular nucleus basalis were therefore determined 4, 24 and 48 h post-lesion. Additionally, the influence of excitotoxic damage on the efficacy of in vivo labelling of cholinergic neurons with carbocyanine 3-192IgG was investigated. Carbocyanine 3-192IgG was unilaterally injected in the lateral ventricle. Twenty-four hours later, NMDA (60 nM/microl) was infused in the right magnocellular nucleus basalis, while control lesions were performed contralaterally. Triple immunofluorescence labelling for carbocyanine 3-192IgG, NMDA receptor 2A and B subunits and choline-acetyltransferase (ChAT) was employed to determine temporal changes in NMDA receptor immunoreactivity on cholinergic neurons. The extent of neuronal degeneration was studied by staining with Fluoro-Jade. Moreover, changes in the numbers of ChAT or p75 low-affinity neurotrophin receptor immunoreactive neurons, and the degree of their co-labelling with carbocyanine 3-192IgG were determined in basal forebrain nuclei. The effects of NMDA-induced lesions on cortical projections of cholinergic nucleus basalis neurons were studied by acetylcholinesterase (AChE) histochemistry. Characteristic signs of cellular damage, as indicated by decreased immunoreactivity for NMDA receptors, ChAT and p75 low-affinity neurotrophin receptors, were already detected at the shortest post-lesion interval investigated. Fluoro-Jade at 4 h post-lesion only labelled the core of the excitotoxic lesion. Longer survival led to enhanced Fluoro-Jade staining, and to the decline of ChAT immunoreactivity reaching a maximum 24 h post-surgery. Significant loss of p75 low-affinity neurotrophin receptor immunoreactivity and of cortical AChE-positive projections only became apparent 48 h post-lesion. Carbocyanine 3-192IgG labelling in the ipsilateral basal forebrain exceeded that of the contralateral hemisphere at all time points investigated and progressively declined in the damaged magnocellular nucleus basalis up to 48 h after NMDA infusion. The present study indicates that excitotoxic lesion-induced alteration of cholinergic neuronal markers is a rapid and gradual process reaching its maximum 24 h post-surgery. Furthermore, in vivo labelling of cholinergic neurons may be applied to indicate neuronal survival under pathological conditions, and enable to follow their degeneration process under a variety of experimental conditions.

Acetylcholine↗

PubMed2001

Oral post-lesion administration of 5-HT(1A) receptor agonist repinotan hydrochloride (BAY x 3702) attenuates NMDA-induced delayed neuronal death in rat magnocellular nucleus basalis.

Recent evidence indicates that stimulation of postsynaptic 5-HT(1A) receptors abates excitotoxic neuronal death. Here we investigated whether oral post-lesion administration of the 5-HT(1A) receptor agonist (-)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochloride (Repinotan HCl) attenuates N-methyl-D-aspartate (NMDA) excitotoxicity (60 nmol/microl) in the rat magnocellular nucleus basalis. Repinotan HCl (1 mg/kg) was administered from day 1, 2, 3, or 6 post-surgery twice daily for five consecutive days. This delayed drug administration protocol was employed to investigate the initiation period during which 5-HT(1A) receptor agonists may significantly influence ongoing neurodegeneration processes. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1 mg/kg) served as reference compound. Twenty-four hours after drug delivery a small open-field test, while on day 14 post-surgery a passive avoidance test was performed. Effects of Repinotan HCl treatment on the survival of cholinergic magnocellular nucleus basalis neurons and their cortical projections were determined by quantitative acetylcholinesterase (AChE) and choline-acetyltransferase (ChAT) histochemistry. Moreover, AChE and ChAT activities were biochemically measured both in the cerebral cortex and in the magnocellular nucleus basalis. Repinotan HCl treatment markedly increased spontaneous activities in the small open-field at any time-point investigated. Improved memory performance was only demonstrated when Repinotan HCl was administered from day 1 post-lesion on wards. Repinotan HCl treatment from day 2 and 3 post-lesion on markedly attenuated both histochemical and neurochemical characteristics of NMDA excitotoxicity on cholinergic magnocellular nucleus basalis neurons and on their cortical projections. Whereas the neuroprotective profile of Repinotan HCl was superior to that of 8-OH-DPAT, oral administration of both 5-HT(1A) receptor agonists yielded largely equivalent behavioral recovery after NMDA infusion in the magnocellular nucleus basalis. In conclusion, the present data indicate the potent neuroprotective action of the 5-HT(1A) receptor agonist Repinotan HCl with a peak efficacy of delayed (2-3 day) post-lesion drug treatment in vivo. Post-lesion treatment with 5-HT(1A) receptor agonists may therefore be of significance in the intervention of neuronal damage associated with acute excitotoxic conditions.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2001

Action of glucocorticoids on survival of nerve cells: promoting neurodegeneration or neuroprotection?

Extensive studies during the past decades provided compelling evidence that glucocorticoids (GCs) have the potential to affect the development, survival and death of neurones. These observations, however, reflect paradoxical features of GCs, as they may be critically involved in both neurodegenerative and neuroprotective processes. Hence, we first address different aspects of the complex role of GCs in neurodegeneration and neuroprotection, such as concentration dependent actions of GCs on neuronal viability, anatomical diversity of GC-mediated mechanisms in the brain and species and strain differences in GC-induced neurodegeneration. Second, the modulatory action of GCs during development and ageing of the central nervous system, as well as the contribution of altered GC balance to the pathogenesis of neurodegenerative disorders is considered. In addition, we survey recent data as to the possible mechanisms underlying the neurodegenerative and neuroprotective actions of GCs. As such, two major aspects will be discerned: (i) GC-dependent offensive events, such as GC-induced inhibition of glucose uptake, increased extracellular glutamate concentration and concomitant elevation of intracellular Ca(2+), decrease in GABAergic signalling and regulation of local GC concentrations by 11 beta-hydroxysteroid dehydrogenases; and (ii) GC-related cellular defence mechanisms, such as decrease in after-hyperpolarization, increased synthesis and release of neurotrophic factors and lipocortin-1, feedback regulation of Ca(2+) currents and induction of antioxidant enzymes. The particular relevance of these mechanisms to the neurodegenerative and neuroprotective effects of GCs in the brain is discussed.

Cell Survival↗

PubMed2001

Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review.

BACKGROUND AND PURPOSE: Based on the results of animal experiments, clinical trials were performed with nimodipine, which did not demonstrate a beneficial effect on outcome after stroke. The aim of this study was to determine whether the evidence from animal experiments with nimodipine supported the use of nimodipine in clinical trials. METHODS: - We performed a systematic review of animal experiments with nimodipine in focal cerebral ischemia. Studies were identified by searching Medline and Embase. We assessed whether these studies showed a beneficial effect of active treatment. In-depth analyses were performed on infarct size and amount of edema, and subgroup analyses were performed on the length of the time window to the initiation of treatment and the methodological quality of the studies. RESULTS: - Of 225 identified articles, 20 studies were included. The methodological quality of the studies was poor. Of the included studies, 50% were in favor of nimodipine. In-depth analyses showed statistically significant effects in favor of treatment (10 studies). No influence of the length of time to the initiation of treatment or of the methodological quality on the results was found. CONCLUSIONS: - We conclude that the results of this review did not show convincing evidence to substantiate the decision to perform trials with nimodipine in large numbers of patients. There were no differences between the results of the animal experiments and clinical studies. Surprisingly, we found that animal experiments and clinical studies ran simultaneously.

Animals↗

PubMed2001

Increased maternal corticosterone levels in rats: effects on brain 5-HT1A receptors and behavioral coping with stress in adult offspring.

This study examined the consequences of elevated corticosterone levels in lactating rats on their offspring's serotonergic 5-hydroxytryptamine (5-HT)1A receptor system and behavioral coping with stress. The mothers received normal drinking water or water with corticosterone, which, via the milk, enters the circulation and brains of the pups. In adulthood, the corticosterone-nursed offspring showed a consistently more passive way of coping with environmental challenges. However, they did not seem to be more anxious. Autoradiographic analysis of the 5-HT1A receptor system revealed a decrease in the adult 5-HT1A receptor binding in the hippocampal CA1 region. The results support the hypothesis that differences in behavioral coping with stress by adult rats are associated with differences in the serotonergic system. At the same time, it suggests that adult coping and its neuronal substrates are not solely determined by genes but depend on subtle developmental factors as well.

Adaptation, Psychological↗

PubMed2000

Postnatal treatment with ACTH-(4-9) analog ORG 2766 attenuates N-methyl-D-aspartate-induced excitotoxicity in rat nucleus basalis in adulthood.

It has been reported that the ACTH-(4-9) analog H-Met(O(2))-Glu-His-Phe-D-Lys-Phe-OH (ORG 2766) administered in adulthood has trophic effects on neuronal tissue and when given postnatally, it can induce long-lasting changes in brain development. In the present study, we investigated whether early postnatal treatment with ORG 2766 affects adult neuronal vulnerability, i.e. the sensitivity of cholinergic neurons against excitotoxic damage. Wistar rat pups received injections of ORG 2766 or saline on postnatal days 1, 3 and 5 and were then left undisturbed until adulthood. At the age of 6 months, the animals were subjected to unilateral lesion of magnocellular basal nucleus by infusion of high dose of N-methyl-D-aspartate (NMDA). The effects of the excitotoxic insult were studied 28 hours and 12 days after the lesion by measuring both the acute cholinergic and glial responses, and the final outcome of the degeneration process. Twenty eight hours after NMDA infusion, postnatally ACTH-(4-9)-treated animals showed stronger suppression of choline-acetyltransferase immunoreactivity and increased reaction of glial fibrillary acidic protein -immunopositive astrocytes in the lesioned nucleus compared to control animals. However, 12 days post-surgery, the NMDA-induced loss of cholinergic neurons, as well as the decrease of their acetylcholinesterase -positive fibre projections in the cortex, were less in ACTH-(4-9) animals. Our data indicate that the early developmental effects of ACTH-(4-9) influence intrinsic neuroprotective mechanisms and reactivity of neuronal and glial cells, thereby resulting in a facilitated rescuing mechanism following excitotoxic injury.

Acetylcholinesterase↗

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

Capillary changes in hippocampal CA1 and CA3 areas of the aging rhesus monkey.

The rhesus monkey is considered a useful animal model for studying human aging, because non-human primates show many of the neurobiological alterations that have been reported in aging humans. Cognitive impairment that accompanies normal aging may, at least partially, originate from capillary changes in the hippocampus, known to be involved in learning and memory. Age-related effects on the cerebral capillaries in the non-human primate hippocampus have not yet been studied. Therefore, we investigated age-related microvascular changes in the hippocampus of the aged non-human primate. We examined by electron microscopy the microvascular ultrastructure in the CAI and CA3 areas of 14 male rhesus monkeys (Macaca mulatta), ranging from 1 to 31 years of age. The percentages of capillaries showing basement membrane thickening and deposits of collagen in the basement membrane were determined semiquantitatively in 4 young (1-6 years), 6 middle-aged (17-24 years), and 4 aged (29-31 years) monkeys. Aberrations in the basement membrane are few in young subjects (28 +/- 6% of capillaries), and occur with increasing frequency during the aging process in rhesus monkeys (aged animals: 71 +/- 5% of capillaries). This could be ascribed to an aging-associated increasing number of capillaries showing depositions of collagen fibrils, rather than local thickenings of the basement membrane. The observed changes in microvascular integrity are very similar to those seen in humans, supporting the view of rhesus monkeys as a model for human aging. The slow but steady progression of these changes could be detrimental for an efficient nutrient supply of the neuropil, and might therefore contribute to decreased cognitive functioning during normal aging.

Aging↗

PubMed2000

Increased amyloid precursor protein expression and serotonergic sprouting following excitotoxic lesion of the rat magnocellular nucleus basalis: neuroprotection by Ca(2+) antagonist nimodipine.

In the present study plastic neural responses to N-methyl-D-aspartate-induced excitotoxic lesions and the neuroprotective effects of the L-type voltage-dependent Ca(2+) channel antagonist nimodipine were investigated in the rat magnocellular nucleus basalis. Assessment of spontaneous behaviour in the elevated plus maze and small open-field paradigms on day 5 and day 14 post-surgery indicated anxiety and persistent hypoactivity of N-methyl-D-aspartate-lesioned rats, as compared with sham-operated controls. Nimodipine administration significantly alleviated the behavioural deficits. Quantitative histochemical analysis of acetylcholinesterase-positive fibre innervation of the somatosensory cortex and determination of the numbers of choline-acetyltransferase-positive proximal fibre branches of cholinergic projection neurons in the magnocellular nucleus basalis demonstrated a severe cholinergic deficit as a consequence of the excitotoxic lesion 14 days post-surgery. Nimodipine pre-treatment significantly attenuated the loss of cortical cholinergic innervation and preserved the functional integrity of cholinergic projection neurons in the magnocellular nucleus basalis. Double-labelling immunocytochemistry demonstrated increased amyloid precursor protein expression in shrinking and presumably apoptotic choline-acetyltransferase-positive neurons, whereas surviving cholinergic nerve cells were devoid of excessive amyloid precursor protein immunoreactivity. Moreover, as a consequence of N-methyl-D-aspartate infusion, rim-like accumulation of amyloid precursor protein-positive astrocytes was visualized in a penumbra-like zone of the excitotoxic injury. Furthermore, abundant sprouting of serotonergic projection fibres invading the damaged magnocellular nucleus basalis subdivision was demonstrated. Pharmacological blockade by the Ca(2+) antagonist nimodipine significantly attenuated both neuronal and glial amyloid precursor protein immunoreactivity and serotonergic fibre sprouting following N-methyl-D-aspartate infusion. The present data characterize plastic endogenous glial and neuronal responses in the magnocellular nucleus basalis model of acute excitotoxic brain damage. The increased amyloid precursor protein expression may indicate effective means of intrinsic neuroprotection, as secreted amyloid precursor protein isoforms are suggested to play a role in neuronal rescue following excitotoxic injury. From a pharmacological point of view, extensive sprouting of serotonergic projections in the damaged magnocellular nucleus basalis may also counteract N-methyl-D-aspartate excitotoxicity via serotonin-induced inhibition of Ca(2+) currents and membrane hyperpolarization. Hence, lesion-induced changes in spontaneous animal behaviour, such as anxiety and novelty-induced hypoactivity, may well be attributed to the considerable re-distribution of serotonergic projections in the basal forebrain. In conclusion, our present data emphasize a role of neuron-glia and neurotransmitter-system interactions in functional recovery after acute excitotoxic brain injury, and the efficacy of L-type Ca(2+) channel blockade by the selective 1,4-dihydropyridine antagonist nimodipine.

Amyloid beta-Protein Precursor↗

PubMed2000

Chronic corticosterone administration dose-dependently modulates Abeta(1-42)- and NMDA-induced neurodegeneration in rat magnocellular nucleus basalis.

The impact of glucocorticoids on beta-amyloid(1-42) (Abeta(1-42)) and NMDA-induced neurodegeneration was investigated in vivo. Abeta(1-42) or NMDA was injected into the cholinergic magnocellular nucleus basalis in adrenalectomized (ADX) rats, ADX rats supplemented with 25%, 100%, 2x100% corticosterone pellets, or sham-ADX controls. Abeta(1-42)- or NMDA-induced damage of cholinergic nucleus basalis neurones was assessed by quantitative acetylcholinesterase histochemistry. Plasma concentrations of corticosterone and cholinergic fibre loss after Abeta(1-42) or NMDA injection showed a clear U-shaped dose-response relationship. ADX and subsequent loss of serum corticosterone potentiated both the Abeta(1-42) and NMDA-induced neurodegeneration. ADX+25% corticosterone resulted in a 10-90 nM plasma corticosterone concentration, which significantly attenuated the Abeta(1-42) and NMDA neurotoxicity. ADX+100% corticosterone (corticosterone concentrations of 110-270 nM) potently decreased both Abeta(1-42)- and NMDA-induced neurotoxic brain damage. In contrast, high corticosterone concentrations of 310-650 nM potentiated Abeta(1-42)- and NMDA-triggered neurodegeneration. In conclusion, chronic low or high corticosterone concentrations increase the vulnerability of cholinergic cells to neurotoxic insult, while slightly elevated corticosterone levels protect against neurotoxic injury. Enhanced neurotoxicity of NMDA in the presence of high concentrations of specific glucocorticoid receptor agonists suggests that the corticosterone effects are mediated by glucocorticoid receptors.

Amyloid beta-Peptides↗

PubMed2000

beta-amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis.

Whereas a cardinal role for beta-amyloid protein (Abeta) has been postulated as a major trigger of neuronal injury in Alzheimer's disease, the pathogenic mechanism by which Abeta deranges nerve cells remains largely elusive. Here we report correlative in vitro and in vivo evidence that an excitotoxic cascade mediates Abeta neurotoxicity in the rat magnocellular nucleus basalis (MBN). In vitro application of Abeta to astrocytes elicits rapid depolarization of astroglial membranes with a concomitant inhibition of glutamate uptake. In vivo Abeta infusion by way of microdialysis in the MBN revealed peak extracellular concentrations of excitatory amino acid neurotransmitters within 20-30 min. Abeta-triggered extracellular elevation of excitatory amino acids coincided with a significantly enhanced intracellular accumulation of Ca2+ in the Abeta injection area, as was demonstrated by 45Ca2+ autoradiography. In consequence of these acute processes delayed cell death in the MBN and persistent loss of cholinergic fibre projections to the neocortex appear as early as 3 days following the Abeta-induced toxic insult. Such a sequence of Abeta toxicity was effectively antagonized by the N-methyl-D-aspartate (NMDA) receptor ligand dizocilpine maleate (MK-801). Moreover, Abeta toxicity in the MBN decreases with advancing age that may be associated with the age-related loss of NMDA receptor expression in rats. In summary, the present results indicate that Abeta compromises neurons of the rat MBN via an excitotoxic pathway including astroglial depolarization, extracellular glutamate accumulation, NMDA receptor activation and an intracellular Ca2+ overload leading to cell death.

Alzheimer Disease↗

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↗

PubMed2000

beta-Amyloid excitotoxicity in rat magnocellular nucleus basalis. Effect of cortical deafferentation on cerebral blood flow regulation and implications for Alzheimer's disease.

Alzheimer's disease is the most common type of dementia with a still largely unclear etiopathology. One of the factors that may directly contribute to the development and progression of the disorder is the abundant accumulation of beta-amyloid peptides (A beta) in senile plaques. In the present account we review coherent in vivo experimental evidence that A beta infusion into the rat magnocellular nucleus basalis (MBN) induces abrupt and persistent behavioral dysfunctions, perturbations of sensory information processing, storage, and retrieval. These substantial behavioral changes are due to the loss of cholinergic neurons in the MBN and their ascending projections to the frontoparietal cortex. Both neuroanatomical and neurochemical observations pin-point that infusion of A beta into the rat basal forebrain significantly decreases choline-acetyltransferase and acetylcholinesterase activities and the population of--probably--M2 muscarinic acetylcholine receptors in the cerebral cortex. Neuropharmacological data indicate that A beta toxicity is mediated by an excitotoxic cascade involving blockade of astroglial glutamate uptake, sustained activation of N-methyl-D-aspartate receptors and an overt intracellular Ca2+ influx. These changes are associated with increased nitric oxide synthase activity in cortical target areas that may directly lead to the generation of free radicals. Besides, as microvessels of the neocortex receive direct input from the MBN we assume that the loss of cholinergic innervation and hence that of tonic cholinergic vasoregulation ultimately leads to disturbances of vascular (endothelial) function and nutrient supply that may directly enhance neuronal vulnerability during aging and in Alzheimer's disease.

Alzheimer Disease↗

PubMed2000

Mechanisms of beta-amyloid neurotoxicity: perspectives of pharmacotherapy.

One of the characteristic neuropathological hallmarks of Alzheimer's disease (AD) is the extracellular accumulation of beta-amyloid peptides (Abeta) in neuritic plaques. Experimental data indicate that different molecular forms of Abeta affect a wide array of neuronal and glial functions and thereby may lead to neuronal death in the nervous system. Whereas the fatal outcome of Abeta overproduction in transgenic cell lines, and of exogenous Abeta administration in numerous neurotoxicity models, is well established, particular facets of a complex molecular cascade by which Abeta attack neural cells are still elusive. In the present review we summarize recent knowledge on mechanisms of Abeta aggregation, its role in Abeta neurotoxicity, and binding of Abeta peptides to putative neuronal and glial receptors. Additionally, an integrative view on the interactions of Ca2+ -mediated excitotoxicity and free radical-induced oxidative stress in Abeta toxicity is provided. Furthermore, we survey advances of pharmacological investigations attempting to prevent and antagonize Abeta toxicity, or to promote neuronal regeneration following Abeta-induced neurotoxic insults. We distinguish two major classes of therapeutic approaches: conventional pharmacotherapy that employs blockade of known receptors, signal transduction pathways, and re-uptake of neurotransmitters, and direct targeting of neurotoxic Abeta by means of beta-sheet breakers, functional anti-Abeta peptides, and antibodies. Although a clinically relevant neuroprotective strategy is not yet available, sequential combination of drug regimens may provide prospects for effective antagonism of late-life Abeta burden and subsequent development of dementia.

Alzheimer Disease↗