Search

Besides a beneficial cardiovascular effect, it was recently suggested that statins can also exert neuroprotective actions. In a previous study, we provided in vitro evidence that lovastatin treatment abates excitotoxic cell death in primary cortical neurons. Here, we investigated the neuroprotective effect of lovastatin in an in vivo mouse model. We found that administration of lovastatin (20 mg/kg) significantly protects cholinergic neurons and their cortical projections against N-methyl-D-aspartate (60 nmol)-induced cell death in the magnocellular nucleus basalis, a neuronal cell group that is characteristically affected in Alzheimer's disease. Furthermore, lovastatin-mediated neuroprotection was shown to be dependent on protein kinase B (PKB)/Akt signaling since treatment with the PKB/Akt inhibitor LY294002 blocked the lovastatin-induced neuroprotective effect. The loss of cholinergic neurons after the lesion in the magnocellular nucleus basalis resulted in memory impairment as tested in a passive avoidance paradigm. This was reverted by pre-lesion lovastatin treatment. From these studies we conclude that treatment with lovastatin may provide protection against neuronal injury in excitotoxic conditions associated with neurodegenerative diseases including Alzheimer's disease.

Although the rabbit brain, in particular the basal forebrain cholinergic system, has become a common model for neuropathological changes associated with Alzheimer's disease, detailed neuroanatomical studies on the morphological organization of basal forebrain cholinergic nuclei and on their output pathways are still awaited. Therefore, we performed quantitative choline acetyltransferase (ChAT) immunocytochemistry to localize major cholinergic nuclei and to determine the number of respective cholinergic neurons in the rabbit forebrain. The density of ChAT-immunoreactive terminals in layer V of distinct neocortical territories and in hippocampal subfields was also measured. Another cholinergic marker, the low-affinity neurotrophin receptor (p75(NTR)), was also employed to identify subsets of cholinergic neurons. Double-immunofluorescence labeling of ChAT and p75(NTR), calbindin D-28k (CB), parvalbumin, calretinin, neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase, or substance P was used to elucidate the neuroanatomical borders of cholinergic nuclei and to analyze the neurochemical complexity of cholinergic cell populations. Cholinergic projection neurons with heterogeneous densities were found in the medial septum, vertical and horizontal diagonal bands of Broca, ventral pallidum, and magnocellular nucleus basalis (MBN)/substantia innominata (SI) complex; cholinergic interneurons were observed in the caudate nucleus, putamen, accumbens nucleus, and olfactory tubercule, whereas the globus pallidus was devoid of cholinergic nerve cells. Cholinergic interneurons were frequently present in the hippocampus and to a lesser extent in cerebral cortex. Cholinergic projection neurons, except those localized in SI, abundantly expressed p75(NTR), and a subset of cholinergic neurons in posterior MBN was immunoreactive for CB and nNOS. A strict laminar distribution pattern of cholinergic terminals was recorded both in the cerebral cortex and in CA1-CA3 and dentate gyrus of the hippocampus. In summary, the structural organization and chemoarchitecture of rabbit basal forebrain may be considered as a transition between that of rodents and that of primates. (C) 2003 Wiley-Liss, Inc.

Although the rabbit brain, in particular the basal forebrain cholinergic system, has become a common model for neuropathological changes associated with Alzheimer's disease, detailed neuroanatomical studies on the morphological organization of basal forebrain cholinergic nuclei and on their output pathways are still awaited. Therefore, we performed quantitative choline acetyltransferase (ChAT) immunocytochemistry to localize major cholinergic nuclei and to determine the number of respective cholinergic neurons in the rabbit forebrain. The density of ChAT-immunoreactive terminals in layer V of distinct neocortical territories and in hippocampal subfields was also measured. Another cholinergic marker, the low-affinity neurotrophin receptor (p75(NTR)), was also employed to identify subsets of cholinergic neurons. Double-immunofluorescence labeling of ChAT and p75(NTR), calbindin D-28k (CB), parvalbumin, calretinin, neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase, or substance P was used to elucidate the neuroanatomical borders of cholinergic nuclei and to analyze the neurochemical complexity of cholinergic cell populations. Cholinergic projection neurons with heterogeneous densities were found in the medial septum, vertical and horizontal diagonal bands of Broca, ventral pallidum, and magnocellular nucleus basalis (MBN)/substantia innominata (SI) complex; cholinergic interneurons were observed in the caudate nucleus, putamen, accumbens nucleus, and olfactory tubercule, whereas the globus pallidus was devoid of cholinergic nerve cells. Cholinergic interneurons were frequently present in the hippocampus and to a lesser extent in cerebral cortex. Cholinergic projection neurons, except those localized in SI, abundantly expressed p75(NTR), and a subset of cholinergic neurons in posterior MBN was immunoreactive for CB and nNOS. A strict laminar distribution pattern of cholinergic terminals was recorded both in the cerebral cortex and in CA1-CA3 and dentate gyrus of the hippocampus. In summary, the structural organization and chemoarchitecture of rabbit basal forebrain may be considered as a transition between that of rodents and that of primates. (C) 2003 Wiley-Liss, Inc.

The effect of aging on 5-HT1A receptor binding in several forebrain areas associated with the basal forebrain cholinergic system was investigated in rats of 3-, 24- and 30-months-old by receptor autoradiography and biochemical binding assay using [H-3]8-OH-DPAT as a ligand. Autoradiographic measurements demonstrated a marked region-specific decline of ligand binding in: (i) regions of the basal forebrain cholinergic cell groups, i.e. the medial septum, diagonal band nuclei and magnocellular nucleus basalis, (ii) the frontal and parietal neocortex and (iii) the dentate gyrus of the hippocampus. No change or- only a slight decrease of the 5-HT1A receptor density was found in other areas investigated: the CA1 and CA3 sectors of hippocampus, the cingular and perirhinal cerebral cortex and the lateral septum. The autoradiographic findings were substantiated by the biochemical binding assay, which revealed a comparable loss of 5-HT1A receptor in the hippocampus and neocortex at the age of 30 months. The results clearly show that with increasing age the decrement of 5-HT1A receptor binding in the rat forebrain is remarkably region-selective and particularly affects the cholinergic cell groups that innervate cortex and hippocampus. This phenomenon appears to be especially significant in relation to the neuronal substrates underlying the age-related alterations of mood and cognition. (C) 1997 Elsevier Science B.V.

The dysfunction and loss of basal forebrain cholinergic neurons and their cortical projections are among the earliest pathological events in the pathogenesis of Alzheimer's disease (AD). The evidence pointing to cholinergic impairments come from studies that report a decline in the activity of choline acetyltransferase (ChAT) and acetylcholine esterase (AChE), acetylcholine (ACh) release and the levels of nicotinic and muscarinic receptors, and loss of cholinergic basal forebrain neurons in the AD brain. Alzheimer's disease pathology is characterized by an extensive loss of synapses and neuritic branchings which are the dominant scenario as compared to the loss of the neuronal cell bodies themselves. The appearance of cholinergic neuritic dystrophy, i.e. aberrant fibers and fiber swelling are more and more pronounced during brain aging and widely common in AD. When taking amyloid-beta (A beta) deposition as the ultimate causal factor of Alzheimer's disease the role of A beta in cholinergic dysfunction should be considered. In that respect it has been stated that ACh release and synthesis are depressed, axonal transport is inhibited, and that ACh degradation is affected in the presence of A beta peptides. beta-Amyloid peptide 1-42, the principal constituent of the neuritic plagues seen in AD patients, is known to trigger excess amount of glutamate in the synaptic cleft by inhibiting the astroglial glutamate transporter and to increase the intracellular Ca(2+) level. Based on the glutamatergic overexcitation theory of AD progression, the function of NMDA receptors and treatment with NMDA antagonists underlie some recent therapeutic applications. Memantine, a moderate affinity uncompetitive NMDA receptor antagonist interacts with its target only during states of pathological activation but does not interfere with the physiological receptor functions. In this study the neuroprotective effect of memantine on the forebrain cholinergic neurons against A beta 42 oligomers-induced toxicity was studied in an in vivo rat dementia model. We found that memantine rescued the neocortical cholinergic fibers originating from the basal forebrain cholinergic neurons, attenuated microglial activation around the intracerebral lesion sides, and improved attention and memory of A beta 42-injected rats exhibiting impaired learning and loss of cholinergic innervation of neocortex. (C) 2010 Elsevier B.V. All rights reserved.

The first part of this article deals with several aspects of efferents and afferents of the rat basal forebrain cholinergic system (BFChS) studied with anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L). PHA-L tracing of the BFChS efferents revealed topographically differentiated axonal trajectories and patterns of presynaptic endings to the neocortex, mesocortex, olfactory nuclei and hippocampus. Combining this method with second immunolabeling, we identified the muscarinic cholinoceptive neurons in the neocortex and the somatostatinergic neurons in the hippocampus as being directly innervated by the magnocellular basal nucleus and the medial septum, respectively. The prefrontal cortex was identified as a source of afferent input to the basal forebrain cholinergic neurons. This projection also exhibits a topographic organization, which shows a reciprocal relationship with the BFChS efferents to the cortex. The second part of this article describes the anatomical changes of cortical cholinergic and some other neurotransmitter systems after long-term cholinergic denervation in the aged rat cortex. The spared cholinergic projection in the largely denervated areas shows abundant malformations, which are similar in appearance to the anatomical alterations of the surviving cholinergic fibers in dementia of the Alzheimer type (AD). Hypertrophic changes also occur in the serotonergic system. The neuropeptide-Y- and somatostatin-containing cortical systems respond with an increment of their axonal densities, in contrast to the decline of these peptides in AD. Although transsynaptic effects are mediated by long-term cholinergic lesions, they do not support the hypothesis that the cholinergic deficiency is a primary event in the pathophysiology of AD.

The first part of this article deals with several aspects of efferents and afferents of the rat basal forebrain cholinergic system (BFChS) studied with anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L). PHA-L tracing of the BFChS efferents revealed topographically differentiated axonal trajectories and patterns of presynaptic endings to the neocortex, mesocortex, olfactory nuclei and hippocampus. Combining this method with second immunolabeling, we identified the muscarinic cholinoceptive neurons in the neocortex and the somatostatinergic neurons in the hippocampus as being directly innervated by the magnocellular basal nucleus and the medial septum, respectively. The prefrontal cortex was identified as a source of afferent input to the basal forebrain cholinergic neurons. This projection also exhibits a topographic organization, which shows a reciprocal relationship with the BFChS efferents to the cortex. The second part of this article describes the anatomical changes of cortical cholinergic and some other neurotransmitter systems after long-term cholinergic denervation in the aged rat cortex. The spared cholinergic projection in the largely denervated areas shows abundant malformations, which are similar in appearance to the anatomical alterations of the surviving cholinergic fibers in dementia of the Alzheimer type (AD). Hypertrophic changes also occur in the serotonergic system. The neuropeptide-Y- and somatostatin-containing cortical systems respond with an increment of their axonal densities, in contrast to the decline of these peptides in AD. Although transsynaptic effects are mediated by long-term cholinergic lesions, they do not support the hypothesis that the cholinergic deficiency is a primary event in the pathophysiology of AD.

The first part of this article deals with several aspects of efferents and afferents of the rat basal forebrain cholinergic system (BFChS) studied with anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L). PHA-L tracing of the BFChS efferents revealed topographically differentiated axonal trajectories and patterns of presynaptic endings to the neocortex, mesocortex, olfactory nuclei and hippocampus. Combining this method with second immunolabeling, we identified the muscarinic cholinoceptive neurons in the neocortex and the somatostatinergic neurons in the hippocampus as being directly innervated by the magnocellular basal nucleus and the medial septum, respectively. The prefrontal cortex was identified as a source of afferent input to the basal forebrain cholinergic neurons. This projection also exhibits a topographic organization, which shows a reciprocal relationship with the BFChS efferents to the cortex. The second part of this article describes the anatomical changes of cortical cholinergic and some other neurotransmitter systems after long-term cholinergic denervation in the aged rat cortex. The spared cholinergic projection in the largely denervated areas shows abundant malformations, which are similar in appearance to the anatomical alterations of the surviving cholinergic fibers in dementia of the Alzheimer type (AD). Hypertrophic changes also occur in the serotonergic system. The neuropeptide-Y- and somatostatin-containing cortical systems respond with an increment of their axonal densities, in contrast to the decline of these peptides in AD. Although transsynaptic effects are mediated by long-term cholinergic lesions, they do not support the hypothesis that the cholinergic deficiency is a primary event in the pathophysiology of AD.

Although the rabbit brain, in particular the basal forebrain cholinergic system, has become a common model for neuropathological changes associated with Alzheimer's disease, detailed neuroanatomical studies on the morphological organization of basal forebrain cholinergic nuclei and on their output pathways are still awaited. Therefore, we performed quantitative choline acetyltransferase (ChAT) immunocytochemistry to localize major cholinergic nuclei and to determine the number of respective cholinergic neurons in the rabbit forebrain. The density of ChAT-immunoreactive terminals in layer V of distinct neocortical territories and in hippocampal subfields was also measured. Another cholinergic marker, the low-affinity neurotrophin receptor (p75(NTR)), was also employed to identify subsets of cholinergic neurons. Double-immunofluorescence labeling of ChAT and p75(NTR), calbindin D-28k (CB), parvalbumin, calretinin, neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase, or substance P was used to elucidate the neuroanatomical borders of cholinergic nuclei and to analyze the neurochemical complexity of cholinergic cell populations. Cholinergic projection neurons with heterogeneous densities were found in the medial septum, vertical and horizontal diagonal bands of Broca, ventral pallidum, and magnocellular nucleus basalis (MBN)/substantia innominata (SI) complex; cholinergic interneurons were observed in the caudate nucleus, putamen, accumbens nucleus, and olfactory tubercule, whereas the globus pallidus was devoid of cholinergic nerve cells. Cholinergic interneurons were frequently present in the hippocampus and to a lesser extent in cerebral cortex. Cholinergic projection neurons, except those localized in SI, abundantly expressed p75(NTR), and a subset of cholinergic neurons in posterior MBN was immunoreactive for CB and nNOS. A strict laminar distribution pattern of cholinergic terminals was recorded both in the cerebral cortex and in CA1-CA3 and dentate gyrus of the hippocampus. In summary, the structural organization and chemoarchitecture of rabbit basal forebrain may be considered as a transition between that of rodents and that of primates. (C) 2003 Wiley-Liss, Inc.