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Daniel M Michaelson

Publications and source records attributed to Daniel M Michaelson.

10 recordsLinked to original sources
PubMed2006

Environmental enrichment stimulates neurogenesis in apolipoprotein E3 and neuronal apoptosis in apolipoprotein E4 transgenic mice.

Neurodegeneration in Alzheimer's disease (AD) is associated with the activation of neurogenesis. The mechanisms underlying this crosstalk between neuronal death and birth and the extent to which it is affected by genetic risk factors of AD are not known. We employed transgenic mice expressing human apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for AD, or expressing human apoE3 (an AD-benign allele), in order to examine the hypothesis that apoE4 tilts the balance between neurogenesis and neuronal cell death in favor of the latter. The results showed an isoform-specific increase in neurogenesis in the hippocampal dentate gyrus (DG) under standard conditions in apoE4-transgenic mice. Environmental stimulation, which increases neurogenesis in the DG of apoE3-transgenic and wild-type mice, had the opposite effect on the apoE4 mice, where it triggered apoptosis while decreasing hippocampal neurogenesis. These effects were specific to the DG and were not observed in the subventricular zone, where neurogenesis was unaffected by either the apoE genotype or the environmental conditions. These in vivo findings demonstrate a linkage between neuronal apoptosis and the impaired neuronal plasticity and cognition of apoE4-transgenic mice, and suggest that similar interactions between apoE4 and environmental factors might occur in AD.

Analysis of Variance↗
PubMed2006

The nucleation growth and reversibility of Amyloid-beta deposition in vivo.

The amyloid-beta (Abeta) peptide is a major constituent of the brain senile plaques that characterize Alzheimer's disease (AD). Converging observations led to the formulation of the amyloid hypothesis whereby the accumulation of soluble aggregates and insoluble Abeta deposits is the primary event in AD pathogenesis. Furthermore, the apoE4 isoform of apolipoprotein E, a major prevalent genetic risk factor of AD, is associated with increased Abeta deposition. To investigate the initial stages of the amyloid cascade in vivo and how this is affected by apoE4, we studied the effects of prolonged inhibition and subsequent reactivation of the Abeta-degrading enzyme, neprilysin, on aggregation and deposition of Abeta in apoE transgenic and control mice. The results revealed that Abeta deposition in vivo is initiated by aggregation of Abeta42, which is followed by reversible deposition of both Abeta42 and Abeta40, along with growth of the deposits, and by their subsequent irreversible fibrillization. The initiation of Abeta42 deposition is accelerated isoform-specifically by apoE4, whereas the growth and dissolution of the Abeta deposits as well as their fibrillization are similarly stimulated by the various apoE isoforms. Interestingly, Abeta deposition was associated with increased gliosis, which may reflect early pathological interactions of beta with the brain's parenchyma.

Alzheimer Disease↗
PubMed2005

Regulation of hippocampal cholesterol metabolism by apoE and environmental stimulation.

Alzheimer's disease is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and it is also affected by environmental factors such as early life education. We have recently shown, utilizing apoE-deficient and apoE transgenic mice, that synaptogenesis in the hippocampus following environmental stimulation is affected by apoE. In view of the pivotal role of cholesterol in synaptic plasticity, and of its suggested role in synaptogenesis, we presently examined the effects of apoE and environmental stimulation on brain cholesterol homeostasis. The hippocampal levels of cholesterol and its precursors and metabolites in control mice were not affected by exposure to environmental stimulation. In contrast, the hippocampal levels of cholesterol and its precursors lathosterol and desmosterol and metabolite 24S-hydroxycholesterol were lower in apoE-deficient mice that were maintained in a regular environmental than those of corresponding control mice, whereas they were markedly elevated following environmental stimulation. Histological and immunohistochemical experiments revealed that the combined stimulatory effects of apoE deficiency and environmental stimulation on cholesterol metabolism were associated with marked activation of hippocampal astrocytes and with the abnormal accumulation of cholesterol in neurons and astrocytes. These effects were rescued similarly in apoE3 and apoE4 transgenic mice. These findings suggest that apoE plays an important role in the translocation of cholesterol from astrocytes to neurons in vivo and in the regulation and homeostasis of this process.

Animals↗
PubMed2005

Apolipoprotein E4 enhances brain inflammation by modulation of the NF-kappaB signaling cascade.

Apolipoprotein E4 (apoE4), the major genetic risk factor of Alzheimer's disease (AD), is associated with enhanced brain inflammation. Genome-wide gene expression profiling was employed to study the effects of apoE genotype on hippocampal gene expression in LPS-treated mice, transgenic for either apoE4 or the AD benign allele, apoE3. This revealed that the expression of inflammation-related genes following intracerebroventricular injection of LPS was significantly higher and more prolonged in apoE4 than in apoE3 transgenic mice. Clustering analysis revealed gene clusters which responded differently in apoE4 and apoE3 mice and were significantly enriched in NF-kappaB response elements. Direct measurement of NF-kappaB-regulated genes revealed that their extent of activation was greater in the apoE4 mice. Immunohistochemistry experiments revealed that microglial and NF-kappaB activation were more pronounced in apoE4 than in apoE3 mice. These findings suggest that the increased brain inflammation in apoE4 mice is related to disregulation of NF-kappaB signaling pathway.

Alzheimer Disease↗
PubMed2005

Brain area- and isoform-specific inhibition of synaptic plasticity by apoE4.

The allele E4 of apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of Alzheimer's disease (AD), inhibits the improvements in learning and memory which result from exposure of apoE transgenic mice to environmental stimulation (ES). In the present study, we investigated the extent to which these cognitive deficits are associated with distinct presynaptic, postsynaptic and axonal impairments and whether these effects are brain area-specific. Exposure to an enriched environment of young mice transgenic for human apoE3, which is the AD benign apoE allele, increased the levels of the presynaptic protein synaptophysin and of the dendritic marker MAP-2 in the hippocampus and entorhinal cortex, whereas the corresponding levels of these proteins in the apoE4 transgenic mice were unaffected by the enriched environment. In contrast, the levels of synaptophysin and MAP-2 in the motor cortex were elevated by environmental stimulation in both the apoE3 and the apoE4 transgenic mice. These findings show that apoE4 inhibits synaptic plasticity following environmental stimulation and that this effect is both isoform- and brain area-specific.

Animals↗
PubMed2004

A nontransgenic mouse model shows inducible amyloid-beta (Abeta) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade.

The amyloid-beta (Abeta) peptide, a major pathological hallmark of Alzheimer's disease (AD), undergoes a cascade of interactions resulting in the formation of soluble aggregates and their conversion in the brain to insoluble deposits and mature senile plaques. Furthermore, the apoE4 isoform of apolipoprotein E (apoE), which is the major genetic risk factor of AD, is associated with increased Abeta deposition. It is not known how the different Abeta aggregates in the amyloid cascade are formed, contribute to the pathogenesis of AD, or are affected by apoE4. To investigate the initial aggregation stages underlying the amyloid cascade in vivo and how apoE affects them, we examined the effects of prolonged inhibition and subsequent reactivation of the Abeta-degrading protease neprilysin on deposition, disaggregation, and fibrillization of Abeta in apoE-transgenic and control mice. In control mice, intracerebroventricular infusion of thiorphan, which inhibits neprilysin, induced Abeta42 and Abeta40 deposition and fibrillization. On termination of thiorphan treatment, the number of Abeta deposits decreased, whereas the fibrillar Abeta deposits were unaffected. Similar treatments in apoE-deficient mice and mice transgenic for human apoE4 or apoE3 revealed that apoE4 enhances specifically the nucleation and aggregation of immunopositive Abeta deposits and that reversible disaggregation of these deposits and their irreversible conversion to fibrillar deposits are stimulated similarly by the different apoE isoforms. Deposition of Abeta and its enhancement by apoE4 were accompanied by increased astrogliosis both far from and near the Abeta deposits, suggesting that astrogliosis might be triggered by both insoluble and soluble Abeta aggregates.

Alzheimer Disease↗
PubMed2003

Human apoE3 but not apoE4 rescues impaired astrocyte activation in apoE null mice.

The allele E4 of apolipoprotein E (apoE) is an important risk factor for Alzheimer's disease (AD) and the chronic brain inflammation which is associated with AD is more pronounced in subjects who carry this allele. In the present study, we employed mice transgenic for the human apoE isoforms apoE3 or apoE4 on a null mouse apoE background and intracerebroventricular injection of LPS to investigate the possibility that the regulation of brain inflammation is affected by the apoE genotype. LPS treatment of control mice resulted in activation of brain astrocytes and microglia whose extent decreased with age. LPS treatment of 6-month-old apoE transgenic and control mice resulted in marked activation of brain astrocytes in the control and apoE3 transgenic mice but had no effect on astrogliosis of age-matched apoE-deficient and apoE4 transgenic mice. In contrast, there were no significant differences between the levels of activated microglia of the apoE3 and apoE4 transgenic mice following LPS treatment. Immunoblot assays revealed that the apoE4 and apoE3 transgenic mice had the same levels of brain apoE, which were similarly increased following LPS treatment. These results show that LPS-induced astrogliosis in apoE transgenic mice is regulated isoform-specifically by apoE3 and not by apoE4 and suggest that similar mechanisms may mediate the phenotypic expression of the apoE4 genotype in AD and in other neurodegenerative diseases.

Age Factors↗
PubMed2003

ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory.

Alzheimer's disease (AD) is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and is affected by environmental factors that include education early in life and socioeconomic background. The extent to which environmental factors affect the phenotypic expression of the AD genetic risk factors is not known. Here we show that the neuronal and cognitive stimulations, which are elicited by environmental enrichment at a young age, are markedly affected by the apoE genotype. Accordingly, exposure to an enriched environment of young mice transgenic for human apoE3, which is the benign AD apoE allele, resulted in improved learning and memory, whereas mice transgenic for human apoE4 were unaffected by the enriched environment and their learning and memory were similar to those of the nonenriched apoE3 transgenic mice. These cognitive effects were associated with higher hippocampal levels of the presynaptic protein synaptophysin and of NGF in apoE3 but not apoE4 transgenic mice. In contrast, cortical synaptophysin and NGF levels of the apoE3 and apoE4 transgenic mice were similarly elevated by environmental enrichment. These findings show that apoE4 impairs hippocampal plasticity and isoform-specifically blocks the environmental stimulation of synaptogenesis and memory. This provides a novel mechanism by which environmental factors can modulate the function and phenotypic expression of the apoE genotype.

Alzheimer Disease↗
PubMed2002

Increased expression of presenilin 2 inhibits protein synthesis.

Mutations in the presenilin genes PS1 and PS2 are a major cause of early onset familial Alzheimer's disease (AD). Previous studies have suggested that presenilins have several functions, including gamma-secretase activity. It was also shown that presenilin expression is increased in the brains of some AD patients and ischemic rodents. The present study examines the effect of increased presenilin expression on protein synthesis. We show here that overexpression of wild-type PS2 (PS2wt) or PS2 mutant containing the FAD mutation N141I (PS2mut) in various cell lines inhibits the synthesis of coexpressed reporter and endogenous proteins. Furthermore, endogenous PS2 seems to be needed for translation inhibition since PS2 null fibroblasts were translationally more active than PS2(+/+) fibroblasts under conditions known to inhibit translation. Overexpression of PS1 also appeared to cause inhibition of protein synthesis, but its effect was much weaker than that of PS2. Taken together, the results suggest that increased expression of PS2 and possibly also of PS1 inhibits translation and that presenilins may function as regulators of protein synthesis.

Actins↗