Neurodegeneration最新文献

Reduced brain glucose utilization in early stages of Alzheimer disease, as measured within vivopositron emission tomography, reflects potentially reversible down-regulation of gene expression for oxidative phosphorylation within neuronal mitochondria. Such down-regulation may occur when neuronal energy demand is first reduced by synaptic dysfunction or loss.

Alzheimer's disease is increasingly seen as an heterogeneous disorder with a variety of molecular pathologies converging on a final common pathway of abnormal amyloid deposition and tau phosphorylation. These result in the appearance of the senile plaques and neurofibrillary tangles and in the subsequent development of a cortical dementia with a prominent memory deficit, reflecting the regional distribution of pathology. Age and mode of onset, additional neurological features and family history have all been used as a basis for classification. A family history has proved most robust with the identification of three genetic loci associated with autosomal dominant familial Alzheimer's disease (FAD). Genetically defined pedigrees are important for exploring the relationships between specific molecular pathology and clinical phenotype and, by following at risk individuals, identifying the earliest features.

It is proposed that pyramidal neurones are central to the pathogenesis and cognitive dysfunction of AD on the basis that they are the site of tangle formation and the mismetabolism of APP and degenerate, and that such cells are the focus of neurotransmitter abnormalities. Anatomical studies in animal and human brain are revealing which neurotransmitter receptors are present on populations of pyramidal neurones and a microdialysis approach has demonstrated the ability of such receptors to alter neuronal activity. Specifically, it is proposed that cholinomi-metics used for the symptomatic treatment of AD may work by influencing the activity of pyramidal neurones and that this action may be potentiated by a 5-HT_1Aantagonist. The contribution of pyramidal neurone transmission failure to the spread of pathology in AD is the subject of continuing investigation.

Presenilin 1 (PS–1) has been identified as the protein encoded by the chromosome 14 locus that, when mutated, leads to familial Alzheimer's disease (FAD). Using PS–1 transfected SHSY5Y neuroblastoma cells, we have demonstrated by immunodetection, using polyclonal antibodies, that PS–1 is processed to give two fragments: an N–terminal 28 kDa fragment, and a C–terminal 18 kDa fragment. In a number of non-transfected cell types, most PS–1 is detected as the cleaved products. The molecular weights of the PS–1 cleavage products suggest that the cleavage point will most probably be within a region of the hydrophilic loop domain coded for by either exon 8 or 9 of the PS–1 gene. The clustering of FAD mutations within exon 8 strongly suggests that it encodes a key functional domain. It seems likely that the cleavage of PS–1 is crucial to some aspect of its functionality. An understanding of this process will give insights into the pathology of AD, and may offer new opportunities for therapeutic intervention.

The calcium-binding protein calbindin-D_28k(CB) is located in midbrain dopaminergic (DA) neurons that are less vulnerable to degeneration in Parkinson's disease and in an animal model of the disorder, the MPTP-treated monkey. The present study sought to determine whether CB-containing DA neurons are also less vulnerable to degeneration in the MPTP-treated mouse. Double-labelling immunocytochemical staining and computer imaging techniques were employed to map and quantify the tyrosine hydroxylase-, CB- and CB-containing tyrosine hydroxylase neurons in portions of nucleus A9 and nucleus A10 (ventral tegmental area and central linear nucleus) following MPTP treatment in the C57BL/6 mouse. A cumulative dose of 140 mg/kg MPTP produced a significantly greater loss of DA neurons that lack CB in both nucleus A9 (71 ± 4%) and the ventral tegmental area (70 ± 4%), compared to the loss of DA neurons that contain CB (44 ± 6% and 25 ± 14%, respectively). In the central linear nucleus there was no loss of CB-containing DA neurons. These data demonstrate that the presence of CB in midbrain DA neurons identifies a population of cells in the mouse that are less vulnerable to MPTP-induced degeneration. The mouse, therefore, can serve as a useful model in which to investigate the putative neuroprotective effects of CB in an animal model of Parkinson's disease.

Experimental lesions using the retrogradely transported toxin, volkensin, have been used in conjunction with autoradiography to investigate the cellular localization of 5–HT_1A, muscarinic M₁and nicotinic receptors. Selective destruction of neocortical pyramidal neurones forming the corticostriatal or corticocortical pathways was achieved by intrastriatal or intracortical injection of volkensin. Selective destruction of layer V corticostriatal neurones was accompanied by loss of binding in the cortex to 5–HT_1Aand muscarinic M₁receptors, and an upregulation of [³H] nicotine binding contralateral to the pyramidal cell loss. Destruction of corticocortical neurones was accompanied by loss of binding to muscarinic and nicotinic receptors. The presence of these cholinoceptors on corticocortical neurones was confirmed by recording carbachol-induced depolarizations from a novel cortical brain slice preparation. It is proposed that cholinoceptors represent a consistent marker for neocortical pyramidal cells, and as such are viable targets for the continuing development of therapies designed to ameliorate the cortical hypoactivity observed in Alzheimer's disease. Ligands for these receptors may also be suitable for positron emission tomography to assess pyramidal neurone numbers in suspected Alzheimer's disease.

We describe nine patients, five women and four men (age at death 58–83 years), who developed isolated progressive frontotemporal dementia over 4 to 12 years. These cases represent nine of the 385 (2.3%) cases from a series of autopsy cases of dementia in a large teaching hospital. One had a mother with a history of frontotemporal dementia and marked frontal lobe atrophy. Another had multiple affected family members with frontotemporal dementia, motor neurone disease or both. None of the nine had clinical evidence of either an upper or lower motor neurone disorder. In each case neuropathological examination revealed cortical pathology identical to that described previously as typical of dementia associated with motor neurone disease. There was variable macroscopic atrophy and neuronal loss in the frontal and temporal lobes. All cases had cortical microvacuolation, in seven limited to cortical layer II, and transcortical in two. There was variable cortical and subcortical gliosis. Intraneuronal ubiquitin-immunoreactive inclusions, characteristic of the extra-motor involvement of motor neurone disease, were found in the hippocampal dentate granule cells and residual neurones in layer II of the frontotemporal cortex of all cases. Similar inclusions were also seen in the nucleus ambiguus of three cases. The hypoglossal nuclei showed no neuronal loss, gliosis or ubiquitin-immunoreactive inclusions. Ubiquitin-immunoreactive dystrophic neurites were detected within affected cortex, being most conspicuous in layer II in areas containing microvacuolation. Dystrophic neurites were not detected in subcortical structures. Spinal cords were unavailable for examination because of limited autopsy consent. The finding of intraneuronal ubiquitin-immunoreactive inclusions characteristic of motor neurone disease in patients with frontotemporal dementia, without clinical or pathological evidence of motor system degeneration, extends the clinical spectrum of diseases associated with such inclusions. We propose the term motor neurone disease-inclusion dementia (MNDID) for these cases.

Cerebral amyloid β protein deposition in Alzheimer's disease is associated with a predominantly local acute phase response that kindles release of various inflammatory and immune system mediators. The molecular events are accompanied by a profound cellular response which is largely orchestrated by microglia. Current evidence suggests microglia are primarily involved in phagocytic activity and may be responsible for inducing further neuronal damage by generating reactive oxygen species and proteolytic enzymes. Antiinflammatory measures that target complement activation as well as microglial-mediated oxidative damage would provide rational therapeutic strategies.

Amyloid β-peptide has been demonstrated to be toxic for primary and clonal neuronal cell linesin vitro. Oxidative mechanisms have been implicated in this pathway at several points, including the aggregation of β-amyloid necessary for cytotoxic activity, generation of radicals by the peptide itself, and intracellularly in response to toxic β-amyloid peptides. Supporting an oxidative hypothesis are the observations that cells mount a stress response to β-amyloid similar to that seen in response to oxidative stress and that they may be rescued from cytotoxicity by antioxidants, inhibitors of oxidative enzyme metabolism, and overexpression of antioxidant enzymes. Although the source(s) of the oxygen radicals has not yet been identified, altered antioxidant enzyme levels and oxidative by-products in Alzheimer's disease brain samples relate thein vitrostudies to the human disease.