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Biomedical subjects

J A Hardy

Publications and source records attributed to J A Hardy.

At least 19 recordsLinked to original sources
PubMed1991

Hereditary cerebral hemorrhage with amyloidosis--Dutch type: its importance for Alzheimer research.

Alzheimer's disease is now commonly regarded as a form of 'amyloid encephalopathy'. Amyloid deposits in the cerebral blood vessels and parenchyma consist mainly of a unique protein called amyloid beta protein (A beta P), which has a molecular weight of 4 kDa and is 42 amino acids long. These deposits are thought to be of pathogenetic importance in Alzheimer's disease. Recently, therefore, attention has been focused on the process of turnover of the precursor of A beta P to amyloid fibrils, and the deposition and persistence of A beta P in this disease. The study of several other diseases with cerebral A beta P deposition can be informative in this respect, because they allow the comparison of different pathogenetic mechanisms that lead to this type of deposition. One of these diseases is hereditary cerebral hemorrhage with amyloidosis- Dutch type (HCHWA-D), which is the subject of this review.

Alzheimer Disease↗
PubMed1991

The multipoint genetic mapping of mouse chromosome 16.

Utilizing a Mus spretus/Mus domesticus (C57BL/10) interspecific backcross, we have constructed a multipoint genetic map of mouse chromosome 16 that extends 43.2 cM from the proximal Prm-1 locus to the distal Ets-2 locus. The genetic map incorporates three new markers: D16Smh6, a random genomic clone; Pgk-1ps1, a phosphoglycerate kinase pseudogene; and the growth-associated protein Gap43. The map position of Gap43 indicates the presence, on mouse chromosome 16, of a significant-size conserved linkage group with human chromosome 3.

Animals↗
PubMed1991

Evidence for allelic heterogeneity in familial early-onset Alzheimer's disease.

Age of onset was examined for 139 members of 30 families affected by early-onset AD. Most (77%) of the variance of age of onset derived from differences between rather than within families. The constancy of age of onset within families was also observed in an analysis restricted to families derived from a population-based epidemiological study with complete ascertainment of early-onset AD. Furthermore, we observed clustering of age of onset within those families that support linkage to the predisposing locus on chromosome 21. Our data are compatible with the view that allelic heterogeneity at the AD locus may account for the similarity in age of onset within families. This finding may be of value for scientific studies of AD as well as for genetic counselling.

Aged↗
PubMed1990

Genetic linkage studies suggest that Alzheimer's disease is not a single homogeneous disorder.

Alzheimer's disease, a fatal neurodegenerative disorder of unknown aetiology, is usually considered to be a single disorder because of the general uniformity of the disease phenotype. Two recent genetic linkage studies revealed co-segregation of familial Alzheimer disease with the D21S1/S11 and D21S16 loci on chromosome 21. But two other studies, one of predominantly multiplex kindreds with a late age-of-onset, the other of a cadre of kindreds with a unique Volga German ethnic origin, found absence of linkage at least to D21S1/S11. So far it has not been possible to discern whether these conflicting reports reflect aetiological heterogeneity, differences in methods of pedigree selection, effects of confounding variables in the analysis (for example, diagnostic errors, assortative matings), or true non-replication. To resolve this issue, we have now examined the inheritance of five polymorphic DNA markers from the proximal long arm of chromosome 21 in a large unselected series of pedigrees with familial Alzheimer's disease. Our data suggest that Alzheimer's disease is not a single entity, but rather results from genetic defects on chromosome 21 and from other genetic or nongenetic factors.

Alzheimer Disease↗
PubMed1990

Amyloid beta protein precursor gene and hereditary cerebral hemorrhage with amyloidosis (Dutch).

Human hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), an autosomal dominant form of cerebral amyloid angiopathy (CAA), is characterized by extensive amyloid deposition in the small leptomeningeal arteries and cortical arterioles, which lead to an early death of those afflicted in their fifth or sixth decade. Immunohistochemical and biochemical studies have indicated that the amyloid subunit in HCHWA-D is antigenically related to and homologous in sequence with the amyloid beta protein isolated from brains of patients with Alzheimer's disease and Down syndrome. The amyloid beta protein is encoded by the amyloid beta protein precursor (APP) gene located on chromosome 21. Restriction fragment length polymorphisms detected by the APP gene were used to examine whether this gene is a candidate for the genetic defect in HCHWA-D. The data indicate that the APP gene is tightly linked to HCHWA-D and therefore, in contrast to familial Alzheimer's disease, cannot be excluded as the site of mutation in HCHWA-D.

Adult↗
PubMed1990

Glutamatergic neurotransmission in Alzheimer's disease.

The studies described here provide convincing evidence of glutamatergic deafferentation in Alzheimer's disease. This deafferentation is presumed to represent the biochemical correlate of pyramidal neuron dysfunction in the disorder. In addition, there is a growing consensus of opinion that there is no widespread depletion of glutamate NMDA receptors in Alzheimer's disease. The significance of glutamatergic neurotransmission abnormalities to the pathogenesis and clinical progression of the disease remains to be established.

Alzheimer Disease↗
PubMed1990

Increased tau messenger RNA in Alzheimer's disease hippocampus.

The microtubule-associated protein tau is present in the pathologic hallmarks of Alzheimer's disease and its production and deposition have been implicated in the pathogenesis of the disease. We detected tau mRNA using in situ hybridization histochemistry in the hippocampus, visual cortex, and cerebellum, and compared its level in Alzheimer's disease with controls. The amount of tau mRNA also was determined as a ratio of total polyadenylated mRNA in each area. A significant and gene-specific increase in tau mRNA hybridization was found in hippocampal fields CA4 and CA3, with a similar trend in the dentate gyrus. In contrast, no change was found in the visual cortex or cerebellum in Alzheimer's disease. Increased hippocampal expression of tau mRNA also was present in cases of non-Alzheimer's dementia. Enhanced tau mRNA may be a marker of attempted plasticity involving the cytoskeleton in neuronal populations affected by various neurodegenerative disorders.

Aged↗
PubMed1990

Physical mapping around the Alzheimer disease locus on the proximal long arm of chromosome 21.

Evidence from linkage studies suggests that familial Alzheimer disease (AD) can be caused by a defect in a gene on the proximal long arm of chromosome 21. We have constructed a physical map spanning 10 megabases of this region of the chromosome by means of pulsed-field gel electrophoresis and analysis of somatic cell hybrids. Our data have allowed us to establish the order of chromosome 21 loci--cen-(S16,S48)-S13-S46-S4-(S52,S110)-(S1,S1 1)--and are thus of immediate relevance both to multipoint linkage analysis in families affected by AD and for moving from this linkage to the isolation of the genetic defect. We have also been able to identify several CpG-rich sequences close to the four most centromeric loci, suggesting the location of genes in this region. These probes, which are all within 1.5 megabases of one another, are currently the markers most tightly linked to the AD locus. Genes identified in this region can therefore be considered as candidates for the disease locus.

Alzheimer Disease↗
PubMed1989

Uptake of gamma-aminobutyric acid and L-glutamic acid by synaptosomes from postmortem human cerebral cortex: multiple sites, sodium dependence and effect of tissue preparation.

The uptake of gamma-aminobutyric acid (GABA) and L-glutamic acid by synaptosomes prepared from frozen postmortem human brain was shown to be effected via distinct high and low affinity sites. At approximately 17 h postmortem delay, the kinetic parameters for GABA uptake were: high affinity site, Km 7.1 +/- 2.5 microM, Vmax 18.7 +/- 4.8 nmol.min-1 per 100 mg protein; low affinity site, Km 2 +/- 1 mM, Vmax 425 +/- 250 nmol.min-1 per 100 mg protein (means +/- S.E.M., n = 13). Kinetic parameters for L-glutamate uptake were: high affinity site, Km 7.5 +/- 1.0 microM, Vmax 85 +/- 8 nmol.min-1 per 100 mg protein; low affinity site, Km 1.8 +/- 1.2 mM. Vmax 780 +/- 175 nmol.min-1 per 100 mg protein (n = 11). A detailed kinetic analysis of high affinity GABA uptake was performed over a range of sodium ion concentrations. The results were consistent with a coupling ratio of one Na+ ion to one GABA molecule; a similar result was found with rat brain synaptosomes. However, rat and human synaptosomes differed in the degree to which the substrate affinity of the high affinity GABA uptake site varied with decreasing Na+ ion concentration. High affinity GABA uptake was markedly affected by the method used to freeze and divide the tissue, but did not vary greatly in different cortical regions. There was some decline of high affinity GABA uptake activity with postmortem delay, apparently due to a loss of sites rather than a change in site affinity.

Adult↗
PubMed1989

1-Methyl-4-phenylpyridinium uptake by human and rat striatal synaptosomes.

1-Methyl-4-phenylpyridinium (MPP+) was taken up into human and rat striatal synaptosomes by a saturable system, similar to that for dopamine, with Km values of 0.24 and 0.17 microM, respectively, and similar Vmax values. Uptake of MPP+ and dopamine into both rat and human synaptosomes was inhibited by cocaine and amfonelic acid, with the latter being five to 10 times more potent than the former. MPP+ uptake was potently inhibited by dopamine in preparations from both species. In general, the characteristics of human and rat synaptosomal MPP+ uptake were very similar It seems unlikely that species differences in toxicity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or reaction to dopamine uptake blockers stem from this system.

1-Methyl-4-phenylpyridinium↗
PubMed1989

Characterisation, density, and distribution of kainate receptors in normal and Alzheimer's diseased human brain.

The specific binding of [3H]kainic acid was investigated in membrane preparations from human parietal cortex obtained postmortem. Saturation studies revealed that binding occurred to a single population of sites with a KD of 15 nM and a Bmax of 110 fmol/mg of protein. The kinetically determined dissociation constant for these sites agreed well with that obtained from saturation analyses. Pharmacological characterisation of these sites gave a profile consistent with those reported for kainate receptor sites in animal brain. The integrity of kainate receptors was studied in several brain regions from six patients who had died of Alzheimer's disease and from six closely matched control subjects. No change in either the affinity or the number of kainate receptors was seen in any of the regions studied, despite the loss of neocortical and hippocampal glutamatergic terminals in the Alzheimer's diseased brains, as previously reported.

Adult↗