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Biomedical subjects

B T Hyman

Publications and source records attributed to B T Hyman.

At least 19 recordsLinked to original sources
PubMed1999

The Alzheimer-related gene presenilin 1 facilitates notch 1 in primary mammalian neurons.

The normal functional neurobiology of the Alzheimer's disease (AD) related gene presenilin 1 (PS1) is unknown. One clue comes from a genetic screen of Caenorhabditis elegans, which reveals that the presenilin homologue sel-12 facilitates lin-12 function [D. Levitan, I. Greenwald, Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene, Nature 377 (1995) 351-355]. The mammalian homologue of lin-12, Notch1, is a transmembrane receptor that plays an important role in cell fate decisions during development, including neurogenesis, but does not have a known function in fully differentiated cells. To better understand the potential role of Notch1 in mammalian postmitotic neurons and to test the hypothesis that Notch and PS 1 interact, we studied the effect of Notch1 transfection on neurite outgrowth in primary cultures of hippocampal/cortical neurons. We demonstrate that Notch1 inhibits neurite extension, and thus has a function in postmitotic mature neurons in the mammalian CNS. Furthermore, we present evidence demonstrating that there is a functional interaction between PS1 and Notch1 in mammalian neurons, analogous to the sel-12/lin-12 interaction in vulval development in C. elegans [D. Levitan, T. Doyle, D. Brousseau, M. Lee, G. Thinakaran, H. Slunt, S. Sisodia, I. Greenwald, Assessment of normal and mutant human presenilin function in Caenorhabditis elegans, Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 14940-14944; D. Levitan, I. Greenwald, Effect of Sel-12 presenilin on Lin-12 localization and function in Caenorhabditis elegans, Development, 125 (1998) 3599-3606]. The inhibitory effect of Notch1 on neurite outgrowth is markedly attenuated in neurons from PS1 knockout mice, and enhanced in neurons from transgenic mice overexpressing wild type PS1, but not mutant PS1. These data suggest that PS1 facilitates Notch1 function in mammalian neurons, and support the hypothesis that a functional interaction exists between PS1 and Notch1 in postmitotic mammalian neurons.

Alzheimer Disease↗
PubMed1999

Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease.

The brains of Alzheimer's disease patients contain extracellular Abeta amyloid deposits (senile plaques). Although genetic evidence causally links Abeta deposition to the disease, the mechanism by which Abeta disrupts cortical function is unknown. Using triple immunofluorescent confocal microscopy and three-dimensional reconstructions, we found that neuronal processes that cross through an Abeta deposit are likely to have a radically changed morphology. We modeled the electrophysiological effect of this changed morphology and found a predicted delay of several milliseconds over an average plaque. We propose that this type of delay, played out among thousands of plaques throughout neocortical areas, disrupts the precise temporal firing patterns of action potentials, contributing directly to neural system failure and dementia.

Aged↗
PubMed1999

Lack of association of presenilin-1 intron-8 polymorphism with neuropathological features of Alzheimer's disease.

Over 45 mutations within the coding region of presenilin-1 (PS-1) are associated with an autosomal dominant form of Alzheimer's disease. Recently allele 1 of a polymorphism within intron-8 was reported to be in disequilibrium with Alzheimer's disease in a group of patients with sporadic Alzheimer's disease. This association has been replicated in some, but not all, studies. To determine whether the PS-1 intronic polymorphism is overrepresented in Alzheimer's disease in an autopsy-proven series, and to examine whether allele 1 is associated with a specific neuropathological phenotype, polymerase chain reaction based technique was used to assess the genotype in 85 cases of Alzheimer's disease. The resulting genotypes were compared with age of onset, duration of illness, and quantitative neuropathological measures of Abeta(total), Abeta(1-40), Abeta(1-42), neurofibrillary tangle number and neuron number. The 1/1 genotype did not associate with any differences in the clinical or neuropathological phenotype. These data suggest that the PS-1 intron-8 polymorphism does not strongly impact the clinical or neuropathologic features of Alzheimer's disease.

Aged↗
PubMed1999

Dynamics of plaque formation in Alzheimer's disease.

Plaques that form in the brains of Alzheimer patients are made of deposits of the amyloid-beta peptide. We analyze the time evolution of amyloid-beta deposition in immunostained brain slices from transgenic mice. We find that amyloid-beta deposits appear in clusters whose characteristic size increases from 14 microm in 8-month-old mice to 22 microm in 12-month-old mice. We show that the clustering has implications for the biological growth of amyloid-beta by presenting a growth model that accounts for the experimentally observed structure of individual deposits and predicts the formation of clusters of deposits and their time evolution.

Alzheimer Disease↗
PubMed1999

Expression and alternate splicing of apolipoprotein E receptor 2 in brain.

Apolipoprotein E isoforms affect the risk of developing Alzheimer's disease. Apolipoprotein E-associated risk may be related to its binding to and clearance by cell surface receptors, including members of the low-density lipoprotein receptor family. We examined the brain expression of the most recently identified member of this receptor family, apolipoprotein E receptor 2, in human brain and placenta. We analysed apolipoprotein E receptor 2 messenger RNA by reverse transcription-polymerase chain reaction and apolipoprotein E receptor 2 protein by immunohistochemistry. Four exons of the apolipoprotein E receptor 2 message were alternately spliced in both fetal and adult brain tissue. Exon 5, encoding three of the seven ligand binding repeats, was absent in the apolipoprotein E receptor 2 messenger RNA examined. Apolipoprotein E receptor 2 messages lacking exon 8, encoding an epidermal growth factor precursor repeat, exon 15, encoding the O-glycosylation region, or exon 18, encoding a cytoplasmic domain, were also present as minor splice variants in the brain and placenta. No differences were observed in the pattern of apolipoprotein E receptor 2 splicing between control and Alzheimer brains. Immunohistochemistry of mouse brain showed that apolipoprotein E receptor 2 was expressed in neurons throughout the brain, with strong expression in pyramidal neurons of the hippocampus, granule cells of the dentate gyrus, cortical neurons and Purkinje cells of the cerebellum. Thus, apolipoprotein E receptor 2 is the fourth apolipoprotein E receptor identified on neuronal cells.

Alternative Splicing↗
PubMed1999

Notch1 inhibits neurite outgrowth in postmitotic primary neurons.

Notch plays an important role in cell fate decisions in uncommitted proliferative cells, including neurogenesis, but is believed to not have a role in postmitotic cells. We have shown previously that Notch1 is highly expressed in embryonal mouse and human brain, but surprisingly it continues to be expressed at low levels in the adult brain. The function of Notch1 in postmitotic neurons in mammals is unknown. To better understand the potential role of Notch1 in mature central nervous system neurons we studied the effect of Notch1 transfection on neurite outgrowth in primary neocortex hippocampal neurons. Transfection at two days in vitro with full length Notch1 inhibited neurite outgrowth. Transfection at five to six days in vitro, after neurite outgrowth was established, led to apparent regression of neurites. These effects were enhanced when truncated constitutively active forms of Notch1 were introduced. Co-transfection with Numb, a physiological inhibitor of Notch, blocked Notch's effect on neurite outgrowth. We also examined whether Notch1 could activate C-promoter binding factor (CBF1) transcription factor using C-promoter binding factor-luciferase constructs, and demonstrated that this signal transduction pathway is present and can be activated in postmitotic neurons. Our results show that in postmitotic neurons Notch1 influences neurite morphology, and can activate its native signal transduction pathway. These data strongly suggest that Notch1 may play a physiologically important role in the central nervous system beyond neurogenesis.

Animals↗
PubMed1999

Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice.

We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP695SWE), which show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in-vitro and in-vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.

Aging↗
PubMed1999

The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors.

To assess the influence of the presenilin 1 (PS1) and 2 (PS2) mutations on amyloid deposition, neurofibrillary tangle (NFT) formation and neuronal loss, we performed stereologically based counts in a high-order association cortex, the superior temporal sulcus, of 30 familial Alzheimer's disease cases carrying 10 different PS1 and PS2 mutations, 51 sporadic Alzheimer's disease cases and 33 non-demented control subjects. All the PS1 and PS2 mutations assessed in this series led to enhanced deposition of total Abeta and Abeta(x-42/43) but not Abeta(x-40) senile plaques in the superior temporal sulcus when compared with brains from sporadic Alzheimer's disease patients. Some of the PS1 mutations studied (M139V, I143F, G209V, R269H, E280A), but not others, were also associated with faster rates of NFT formation and accelerated neuronal loss in the majority of the patients who harboured them when compared with sporadic Alzheimer's disease patients. In addition, our analysis showed that dramatic quantitative differences in clinical and neuropathological features can exist even among family members with the identical PS mutation. This suggests that further individual or pedigree genetic or epigenetic factors are likely to modulate PS phenotypes strongly.

Age of Onset↗
PubMed1999

Risperidone treatment of behavioral disturbances in outpatients with dementia.

The authors retrospectively assessed the effectiveness and side effects of risperidone used to treat behavioral disturbances in elderly outpatients with dementia. In 41 patients treated with risperidone 1.8 +/- 1.4 mg/day, there was complete suppression of the target symptom in 15%, partial response in 41%, and no response in 44%. Risperidone appeared equally effective in treating agitation and psychosis. New or worsening extrapyramidal side effects (EPS) occurred in 32%, associated with longer duration of treatment and possibly with concomitant use of serotonergic anti-depressants. Risperidone was a useful adjunct in the treatment of agitation and psychosis in outpatients with dementia but was limited by EPS in about one-third of patients.

Age Factors↗
PubMed1999

Chemokines/chemokine receptors in the central nervous system and Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, and the fourth leading cause of death in the United States. Its pathological changes include amyloid beta deposits, neurofibrillary tangles and a variety of 'inflammatory' phenomenon such as activation of microglia and astrocytes. The pathological significance of inflammatory responses elicited by resident central nervous system (CNS) cells has drawn considerable attention in recent years. Chemokines belongs to a rapidly expanding family of cytokines, the primary function of which is control of the correct positioning of cells in tissues and recruitment of leukocytes to the site of inflammation. Study of this very important class of inflammatory cytokines may greatly help our understanding of inflammation in the progress of AD, as well as other neurodegenerative diseases. So far, immunoreactivity for a number of chemokines (including IL-8, IP-10, MIP-1beta, MIPalpha and MCP-1) and chemokine receptors (including CXCR2, CXCR3, CXCR4, CCR3, CCR5 and Duffy antigen) have been demonstrated in resident cells of the CNS, and upregulation of some of the chemokines and receptors are found associated with AD pathological changes. In this review, we summarize findings regarding the expression of chemokines and their receptors by CNS cells under physiological and pathological conditions. Although little is known about the potential pathophysiological roles of chemokines in CNS, we have put forward hypotheses on how chemokines may be involved in AD.

Alzheimer Disease↗
PubMed1998

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride neurotoxicity is attenuated in mice overexpressing Bcl-2.

The proto-oncogene Bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that Bcl-2 protects against free radicals and that it increases mitochondrial calcium-buffering capacity. The neurotoxicity of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyride (MPTP) is thought to involve both mitochondrial dysfunction and free radical generation. We therefore investigated MPTP neurotoxicity in both Bcl-2 overexpressing mice and littermate controls. MPTP-induced depletion of dopamine and loss of [3H]mazindol binding were significantly attenuated in Bcl-2 overexpressing mice. Protection was more profound with an acute dosing regimen than with daily MPTP administration over 5 d. 1-Methyl-4-phenylpyridinium (MPP+) levels after MPTP administration were similar in Bcl-2 overexpressing mice and littermates. Bcl-2 blocked MPP+-induced activation of caspases. MPTP-induced increases in free 3-nitrotyrosine levels were blocked in Bcl-2 overexpressing mice. These results indicate that Bcl-2 overexpression protects against MPTP neurotoxicity by mechanisms that may involve both antioxidant activity and inhibition of apoptotic pathways.

1-Methyl-4-phenylpyridinium↗
PubMed1998

Immunohistochemical and in situ analysis of amyloid precursor-like protein-1 and amyloid precursor-like protein-2 expression in Alzheimer disease and aged control brains.

Amyloid precursor protein (APP) is a ubiquitously expressed membrane spanning glycoprotein which is endoproteolytically processed to Abeta, a 39-43 amino acid peptide that is the main component of senile plaques in Alzheimer Disease (AD). APP is a member of a highly conserved gene family, including Amyloid Precursor-Like Proteins (APLPs) APLP1 and APLP2. We now characterize APLP1 and APLP2 mRNA and protein expression in AD and aged control brains. Using in situ hybridization in hippocampal tissue from control and AD brain, we show that APLP1 and APLP2 mRNA are expressed primarily in the granule cells of the dentate gyrus, in areas CA1-CA3, and subiculum. Immunohistochemistry reveals staining for both APLP1 and APLP2 in neurons and blood vessels in AD and control cases. In addition, in AD brain, large dystrophic neurites in a subset of senile plaques are conspicuously labeled with APLP1 and APLP2 antibodies. The aged control brains have significantly fewer immunoreactive plaques and dystrophic neurites. The regional, cellular, and subcellular distribution of APLP1 and APLP2 overlap with each other and with APP. These observations support the hypothesis that the members of this family of proteins may perform similar functions.

Aged↗
PubMed1998

Lack of specific association of presenilin 1 (PS-1) protein with plaques and tangles in Alzheimer's disease.

Missense mutations in the presenilin-1 (PS-1) gene are causally related to the majority of familial early-onset Alzheimer's disease (FAD). PS-1 immunohistochemical expression in normal human brain and in brains with Alzheimer's disease (AD) has so far been controversial. Here, we report a study of PS-1 expression in brains, cell lines and peripheral blood mononuclear cells using a panel of well characterized PS-1-specific antibodies. These antibodies were characterized by immunofluorescent staining of PS-1 transfectants followed by flow cytometric analysis. In human brain, widespread neuronal staining was observed. PS-1 immunoreactivity was primarily confined to neuronal cell bodies and proximal dendrites. Weaker staining of microglia was also detected, in accord with the finding of PS-1 immunoreactivity in monocytes. PS-1 expression is not particularly associated with neurons either containing or spared from neurofibrillary tangles, nor with senile plaques. The level of PS-1 expression does not differ between normal and AD brains. Immunoprecipitation from AD, FAD and control brains revealed only a 32 kDa N-terminal fragment and an 18-20 kDa C-terminal fragment. Little or no full length PS-1 was detected. The enriched presence of PS-1 in neurons implies an important role in neuronal function, however, the lack of apparent association of its expression with AD pathology signifies the need for a better understanding of its pathophysiological role.

Alzheimer Disease↗
PubMed1998

Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease.

BACKGROUND: The epsilon4 allele of the gene encoding apolipoprotein E (APOE) is strongly associated with Alzheimer's disease, but its value in the diagnosis remains uncertain. METHODS: We reviewed clinical diagnoses and diagnoses obtained at autopsy in 2188 patients referred to 1 of 26 Alzheimer's disease centers for evaluation of dementia. The sensitivity and specificity of the clinical diagnosis or the presence of an APOE epsilon4 allele were calculated, with pathologically confirmed Alzheimer's disease used as the standard. The added value of the APOE genotype was estimated with pretest and post-test probabilities from multivariate analyses to generate receiver-operating-characteristic curves plotting sensitivity against the false positive rate. RESULTS: Of the 2188 patients, 1833 were given a clinical diagnosis of Alzheimer's disease, and the diagnosis was confirmed pathologically in 1770 patients at autopsy. Sixty-two percent of patients with clinically diagnosed Alzheimer's disease, as compared with 65 percent of those with pathologically confirmed Alzheimer's disease, had at least one APOE epsilon4 allele. The sensitivity of the clinical diagnosis was 93 percent, and the specificity was 55 percent, whereas the sensitivity and specificity of the APOE epsilon4 allele were 65 and 68 percent, respectively. The addition of information about the APOE genotype increased the overall specificity to 84 percent in patients who met the clinical criteria for Alzheimer's disease, although the sensitivity decreased. The improvement in specificity remained statistically significant in the multivariate analysis after adjustment for differences in age, clinical diagnosis, sex, and center. CONCLUSIONS: APOE genotyping does not provide sufficient sensitivity or specificity to be used alone as a diagnostic test for Alzheimer's disease, but when used in combination with clinical criteria, it improves the specificity of the diagnosis.

Aged↗
PubMed1998

Apolipoprotein E genotype and deposits of Abeta40 and Abeta42 in Alzheimer disease.

OBJECTIVE: To examine the differential deposition of amyloid beta (Abeta) peptide isoforms Abeta40 and Abeta42 in the Alzheimer disease (AD) brain in relation to the apolipoprotein E (APOE) genotype. BACKGROUND: The APOE epsilon4 genotype is an inherited risk factor for AD and is associated with increased deposition of Abeta protein in the cerebral cortex. Previous data from familial AD due to mutations in presenilin 1 and presenilin 2 genes and the amyloid precursor protein suggest that the long form of Abeta peptide, Abeta42, is selectively increased in these circumstances. Herein, we examine whether APOE genotype influenced the species of Abeta peptide deposited. DESIGN AND METHODS: The amount of Abeta40, Abeta42, and total Abeta deposited in immunostained temporal lobe tissue of 28 cases of AD of known APOE genotype was determined. RESULTS: Individuals with the APOE epsilon4 genotype (APOE epsilon4/4) were associated with both increased Abeta40 (P<.05) and Abeta42 (P<.05) compared with individuals without the APOE epsilon4/4 genotype. CONCLUSION: Our results differ from the data from AD due to mutations in presenilin 1 and presenilin 2 genes and the amyloid precursor protein and suggest that the APOE epsilon4 genotype mediates increased Abeta deposition by a mechanism that differs from that found in other genetic causes of AD.

Aged↗
PubMed1998

Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different APOE genotypes.

Recent data have implicated apolipoprotein E (apoE) in neuritic outgrowth, synaptic stability, and Alzheimer's disease; these data led us to examine the normal role of apoE-containing lipoproteins in the central nervous system (CNS). We isolated lipoproteins from human cerebrospinal fluid (CSF) in order to examine their composition and potential functions. CSF particles were composed of approximately one-third protein, one-third phospholipid, and one-third cholesterol. ApoE3 formed homodimers and heterodimers with apoA-II, while apoE4, as expected, was monomeric. We addressed the function of CSF lipoproteins with assays of cholesterol efflux and cholesterol influx. CSF lipoproteins decreased intracellular levels of cholesterol in cholesterol-loaded fibroblasts, suggesting these particles can act to remove excess lipids from cells. CSF lipoproteins competed for 125I-labeled LDL degradation by fibroblasts, suggesting they can also interact with the LDL receptor. Furthermore, CSF lipoproteins labeled with the fluorescent dye Dil were internalized by neuroglioma cells and primary neurons and astrocytes in culture. Together, these data support a model of CSF lipoproteins acting to remove lipids from degenerating cells and delivering lipids to cells for new membrane synthesis or storage.

Aged↗
PubMed1998

Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer's disease brains.

Chemokines belong to an expanding family of cytokines the primary function of which is recruitment of leukocytes to inflammatory sites. Recent evidence has shown their presence in the central nervous system. Because inflammatory responses have been implicated in the pathogenesis of Alzheimer's disease (AD), we studied the expression of CCR3, CCR5, and their ligands in normal and AD brains by immunohistochemistry. CCR3 and CCR5 are present on microglia of both control and AD brains, with increased expression on some reactive microglia in AD. Immunohistochemistry for MIP-1beta, MIP-1alpha, RANTES, eotaxin, and MCP-3 (ligands for CCR5 and/or CCR3) revealed the presence of MIP-1beta predominantly in a subpopulation of reactive astrocytes, which were more widespread in AD than control brains, and MIP-1alpha predominantly in neurons and weakly in some microglia in both AD and controls. Many of the CCR3+ or CCR5+ reactive microglia and MIP-1beta+ reactive astrocytes were found associated with amyloid deposits. Immunoreactivity for eotaxin, RANTES, and MCP-3 were not detected. Detection of these beta-chemokine receptors on microglia and some of their ligands in reactive astrocytes and neurons as well as microglia suggests a role for this system in glial-glial and glial-neuronal interactions, potentially influencing the progression of AD.

Adult↗