Neurodegeneration最新文献

We have examined the distribution and composition of gangliosides in central and peripheral nervous tissues from two patients with Creutzfeldt-Jakob disease (CJD). There were marked decreases in total ganglioside levels in CJD, with reductions in the cerebral cortex and cerebellum in the order of 20–30% and 50% of control values, respectively, though in spinal cord and sciatic nerve total gangliosides were not significantly altered. The percentage distribution of individual gangliosides was characterized by marked increases in GD3 and GD2, contrasting with severe decreases in GD1a, GD1b, GT1b and GQ1b; such changes were found throughout the patients' nervous tissues. An abnormal long-chain base composition was detected with the d20:1 component being decreased to less than 50% of control values, in the cerebrum, cerebellum and spinal cord. Changes in gangliosides occurred even in those tissues not severely affected neuropathogically. These ganglioside abnormalities are discussed in relationship to the pathogenesis of CJD.

Information about the outside world is carried into the hippocampus by glutamatergic pyramidal cell pathways from the posterior association cortex via the subiculum. Processed information is carried away from the hippocampus by a reciprocal glutamatergic pathway back into posterior association cortex. These pathways are thought to be crucial for the acquisition of long term memories although it seems likely that memories are stored in cortex rather than within the hippocampus. The hippocampus is supported by functionally excitatory cholinergic modulation via fornical afferents and by functionally inhibitory serotonergic modulation specifically via 5HT_1Areceptors. Cholinergic modulation of the hippocampus is necessary for efficient acquisition of visuospatial tasks but not for retention of similar tasks first acquired prior to surgery. Cholinergic modulation of areas outside the hippocampus may contribute to the maintenance of memories and non-cholinergic efferents in the fornix may be required for retrieval of tasks first learnt when the hippocampus was intact. Impairments on acquisition of visuospatial tasks brought about by fornix transection can be ameliorated by direct stimulation of cholinergic receptors using pilocarpine or by blockade of the serotonergic inhibitory modulation of the hippocampus using the 5HT_1Areceptor antagonist, WAY100635, indicating an equal-but-opposite modulatory effect of these two neurotransmitters on hippocampal function.

Brain amyloid deposits play a central role in the histopathology of Alzheimer's disease (AD), as evidenced by increased formation of amyloid β peptides (Aβ) in genetic forms of AD that are caused by mutations in the presenilin genes, or the amyloid β protein precursor (APP) gene. Neuronal deafferentation in AD brain may also be associated with accelerated Aβ formation, because APP processing is regulated by neuronal activity, presumably via several G protein-coupled neurotransmitter receptors. Subtype-selective agonists including muscarinic m1 receptor ligands may be useful for the pharmacological reduction of Aβ formation.

Neurofibrillary pathology is seen in a wide variety of disorders such as Alzheimer's disease (AD), progressive supranuclear palsy and the Parkinsonism-dementia amyotrophic lateral sclerosis complex of Guam. To assess the pathological importance of these lesions quantitative studies need to be undertaken. To date, most neuropathological studies have been based on qualitative, or at best semi-quantitative, data reporting the presence or absence of specific lesion types. To obtain such data traditionally involves laborious manual measurements, which rely heavily on the skill of the investigator and tend to have low inter- and intra-rater reliabilities. We have developed a novel analysis technique, using colour image analysis, which can accurately quantify the total amount of neurofibrillary damage present. Furthermore we have developed a set of mathematically defined morphological criteria to allow objective discrimination between the three types of neurofibrillary damage seen in the cortex immunostained with Alz–50. Use of this novel technique provides a reliable, rational means for the classification of neurofibrillary lesions.

The expression of the presenilin 1 (PS–1) gene has been investigated byin situhybridization in early onset familial Alzheimer's disease (FAD), late onset Alzheimer's disease (AD) and normal control brain. Mutations in this gene are responsible for chromosome 14–linked FAD. We have found that presenilin 1 mRNA is present throughout the human brain with a distribution consistent with both a glial and neuronal localization. Thein situhybridization pattern was similar for the controls, the early onset FAD cases and the late onset AD cases. However, one of the two forms of the mRNA for PS–1, the long form (which contains a sequence encoding a four amino acid (VRSQ) insert at its 5′end) was significantly reduced in early onset FAD brain compared with late onset AD. We suggest that this long transcript may alter the normal pathway for processing of amyloid precursor protein, the protein which appears to be central in the pathogenesis of AD.

The neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is commonly used as a chemical tool to induce selective denervation of noradrenergic terminals arising from the locus coeruleus and to study the molecular mechanisms underlying degeneration of central noradrenergic axons in rodents. Monoamine depletion in different rodent species after DSP-4 is generally assumed to occur with a similar pattern. To verify this assumption, in the present study we evaluated the different patterns of monoamine depletion produced by DSP-4 in different brain regions of two different strains of mice and rats 3, 7 and 14 days after DSP-4 administration. In this report, we show that there are evident species and strain differences concerning the pattern of norepinephrine depletion in various brain regions. Moreover, serotonin levels are fully preserved following DSP-4 in mice, whereas there is a significant serotonin decrease in specific brain regions after the same dose of DSP-4 in rats. Apart from disclosing species and strain variability among rodents in neurotoxin-induced monoamine depletion, these findings suggest that DSP-4 should be considered as a different neurotoxin, depending on the species and strain in which it is administered.

The purpose of the present study was to examine and quantify the functional consequence of a focal cerebral ischaemic lesion in a primate species, the marmoset. Following craniotomy and retraction of the frontal and temporal lobes, the middle cerebral artery was permanently occluded by means of electrocoagulation. Three and eight weeks after surgery, various behavioural tests were used to give a quantifiable measure to the neurological deficits produced. These tests required the monkeys to reach into tubes for foodbits, retrieve rewards from the steps of two designs of «staircases», respond to one of two simultaneously presented rewarded tubes, remove adhesive labels attached to their feet, and respond to sensory stimuli. Unilateral motor impairment of the contralateral forelimb and neglect of contralateral tactile stimuli were seen in all subjects, and spatial neglect was also present in some monkeys. Subsequent histological analysis revealed unilateral cortical damage in all subjects with varying amounts of injury to the caudate and the putamen in some animals. These results demonstrate the potential for the use of this species in future investigations to examine the effect of neuroprotective treatment on functional outcome after a focal ischaemic insult.

Recent studies suggest that mutations in the presenilin 1 gene, which encodes a polypeptide predicted to be a multispanning membrane protein, are responsible for the majority of cases of early onset, autosomal dominant Alzheimer's disease. Here we describe a further mutation in the presenilin 1 gene (R269G) in a family with early onset Alzheimer's disease. This mutation is in exon 8 which appears to be a favoured region for pathogenic mutations. In the presenilin protein the region coded for by this exon is likely to comprise a domain located on the membrane surface. We discuss the likely effects of the exon 8 mutations on the structure of the exon and in the pathogenesis of the disease.

Neurofibrillary lesions such as neurofibrillary tangles, neurites and neuropil threads are used as neuropathological markers of Alzheimer's disease (AD). However these lesions are also seen in non-demented elderly cases as well as in several other disorders such as Down's syndrome (DS), dementia pugilistica (DP) and Parkinson's disease. Quantitative studies may therefore help in understanding the pathophysiological role of these lesions. Using a novel image analysis technique we have quantified the extent of neurofibrillary damage in AD, DS and DP. We have found that the extent of neurofibrillary change did not significantly differ beween AD and DS, though there were also strong parallels between AD and DP. We conclude that both genetic (as in DS) and environmental (as in DP) risk factors for AD-type pathology provide a similar pattern of neurofibrillary degeneration to that in AD itself suggesting that similar degenerative mechanisms might be triggered in all three conditions.

We have examined MPTP toxicity to dopamine neurons of mice homozygous for a transgenic knockout of the p53 growth control gene (p53^−/−). MPTP at a total dose of 96 mg/kg administered in four doses over two days produced a non-homogeneous loss of striatal dopamine transport sites and quantitatively reduced 3H–mazindol binding to similar degrees in p53^−/−and wild type controls 2 and 3 weeks after starting MPTP. Nigral DA neurons stained immunohistochemically for tyrosine hydroxylase were counted using both manual and automated methods and found to be reduced 29—34% in wild type controls but were not reduced in p53^−/−. Mean DA neuronal surface areas were reduced 63—68% by MPTP in controls and 35—50% in p53^−/−. We conclude that p53 protein appears necessary for complete expression of MPTP neurotoxicity to dopamine neurons. Our findings suggest that the p53 gene and other growth control genes may regulate dopamine neuronal death in PD.