A5078489763- Alzheimer's disease research and treatments
- Cholesterol and Lipid Metabolism
- Drug Transport and Resistance Mechanisms
- Neuroinflammation and Neurodegeneration Mechanisms
- Peroxisome Proliferator-Activated Receptors
- Nuclear Receptors and Signaling
- Inflammation biomarkers and pathways
- MicroRNA in disease regulation
- RNA modifications and cancer
- Retinoids in leukemia and cellular processes
- Extracellular vesicles in disease
- Gestational Trophoblastic Disease Studies
- Peptidase Inhibition and Analysis
- Epigenetics and DNA Methylation
- Adenosine and Purinergic Signaling
- Cardiovascular Issues in Pregnancy
- Advanced biosensing and bioanalysis techniques
- Cancer therapeutics and mechanisms
- Adipose Tissue and Metabolism
- DNA Repair Mechanisms
- Immune cells in cancer
- Biological Research and Disease Studies
- Arsenic contamination and mitigation
- Trace Elements in Health
- Genetics and Neurodevelopmental Disorders
University of Pittsburgh
2015-2024
UPMC Hillman Cancer Center
1998-2003
St. John's School
1996
Trakia University
1992
During the development of in vivo amyloid imaging agents, an effort was made to use micro-positron emission tomography (PET) presenilin-1 (PS1)/amyloid precursor protein (APP) transgenic mouse model CNS deposition screen new compounds and further study Pittsburgh Compound-B (PIB), a PET tracer that has been shown be retained well amyloid-containing areas Alzheimer's disease (AD) brain. Unexpectedly, we saw no significant retention PIB this even at 12 months age when PS1/APP typically exceeds...
ABCA1 (ATP-binding cassette transporter A1) is a major regulator of cholesterol efflux and high density lipoprotein (HDL) metabolism. Mutations in human cause severe HDL deficiencies characterized by the virtual absence apoA-I prevalent atherosclerosis. Recently, it has been reported that lack causes significant reduction apoE protein level brain knock-out (ABCA1-/-) mice. ApoE isoforms strongly affect Alzheimer disease (AD) pathology risk. To determine further effect on amyloid deposition,...
Recent studies indicate that oxysterols, which are ligands for the nuclear hormone liver X receptors (LXR), decrease amyloid beta (Abeta) secretion in vitro. The effect was attributed primarily to ATP-binding cassette transporter A1 (ABCA1) transcriptionally up-regulated by ligand-activated LXRs. We now examined of synthetic LXR ligand T0901317, can be used vivo, on Abeta production vitro and APP23 transgenic mice. T0901317 applied a variety models, including immortalized fibroblasts from...
The ATP-binding cassette transporter A1 (ABCA1) is a major regulator of peripheral cholesterol efflux and plasma high density lipoprotein metabolism. In adult rat brain we found expression ABCA1 in neurons the hypothalamus, thalamus, amygdala, cholinergic basal forebrain, hippocampus. Large nucleus basalis together with CA1 CA3 pyramidal were among most abundantly immunolabeled neurons. Glia cells largely negative. Because homeostasis may have an essential role central nervous system...
High-fat diet and certain dietary patterns are associated with higher incidence of sporadic Alzheimer's disease (AD) cognitive decline. However, no specific therapy has been suggested to ameliorate the negative effects high fat/high cholesterol levels on cognition amyloid pathology. Here we show that in 9-month-old APP23 mice, a high-fat/high-cholesterol (HF) provided for 4 months exacerbates AD phenotype evaluated by behavioral, morphological, biochemical assays. To examine therapeutic...
ATP-binding cassette transporter A1 (ABCA1) regulates cholesterol efflux and is an essential mediator of high-density lipoprotein (HDL) formation. In amyloid precursor protein (APP) transgenic mice, Abca1 deficiency increased deposition in the brain paralleled by decreased levels Apolipoprotein E (ApoE). The APOE ε 4 allele major genetic risk factor sporadic Alzheimer's disease (AD). Here, we reveal effect on phenotype mice expressing human ApoE3 or ApoE4. We used APP/E3 APP/E4 generated...
While the risks of maternal alcohol abuse during pregnancy are well-established, several preclinical studies suggest that chronic preconception consumption by either parent may also have significance consequences for offspring health and development. Notably, since isogenic male mice used in these not involved gestation or rearing offspring, cross-generational effects paternal exposure a germline-based epigenetic mechanism. Many recent demonstrated environmental exposures such as stress...
Abstract APOE and Trem2 are major genetic risk factors for Alzheimer’s disease (AD), but how they affect microglia response to Aβ remains unclear. Here we report an isoform-specific phospholipid signature with correlation between human APOEε3/3 APOEε4/4 AD brain lipoproteins from astrocyte conditioned media of APOE3 APOE4 mice. Using preclinical mouse models, show that lipoproteins, unlike APOE4, induce faster microglial migration towards injected Aβ, facilitate uptake, ameliorate effects on...
A hallmark of Alzheimer disease (AD) is the deposition amyloid β (Aβ) in brain parenchyma and cerebral blood vessels, accompanied by cognitive decline. Previously, we showed that human apolipoprotein A-I (apoA-I) decreases Aβ(40) aggregation toxicity. Here demonstrate apoA-I lipidated or non-lipidated form prevents formation high molecular weight aggregates Aβ(42) toxicity primary cells. To determine effects on AD phenotype vivo, crossed APP/PS1ΔE9 to apoA-I(KO) mice. Using a Morris water...
Chronic exposure to arsenic in drinking water, especially utero or perinatal exposure, can initiate neurological and cognitive dysfunction, as well memory impairment. Several epidemiological studies have demonstrated learning deficits children with early low moderate levels of arsenic, but pathogenic mechanisms etiology for these are poorly understood. Since vivo show a role histone acetylation performance formation, we examined if prenatal causes changes the epigenomic landscape. We exposed...
We examined the effect of chronic high fat diet (HFD) on amyloid deposition and cognition 12-months old APP23 mice, correlated phenotype to brain transcriptome lipidome. HFD significantly increased plaques worsened cognitive performance compared mice normal (ND). RNA-seq results revealed that in there was an expression genes related immune response, such as Trem2 Tyrobp. found a significant increase TREM2 immunoreactivity cortex response HFD, most pronounced female pathology. Down-regulated...
Abstract Background The application of advanced sequencing technologies and improved mass-spectrometry platforms revealed significant changes in gene expression lipids Alzheimer’s disease (AD) brain. results so far have prompted further research using “multi-omics” approaches. These approaches become particularly relevant, considering the inheritance APOEε4 allele as a major genetic risk factor AD, protective effect APOEε2 allele, role APOE brain lipid metabolism. Methods Postmortem samples...
Abstract Background Alzheimer’s Disease (AD) is a neurodegenerative disorder influenced by aging and genetic risk factors. The inheritance of APOE ε4 variants Triggering Receptor Expressed on Myeloid cells 2 ( TREM2 ) are major factors for AD. Recent studies showed that binds to TREM2, thus raising the possibility an APOE-TREM2 interaction can modulate AD pathology. Methods aim this study was investigate using complex model mice - crossbreed Trem2 ko APP/PSEN1dE9 expressing human APOE3 or...
Amyloid precursor protein (APP) is the source of neurotoxic amyloid β (Aβ) peptide associated with Alzheimer's disease. Apolipoprotein A-I (apoA-I), a constituent high-density lipoprotein complexes, was identified by yeast two-hybrid system as strong and specific binding partner full-length APP (APPfl). This association between apoA-I APPfl localized to extracellular domain (APPextra). Furthermore, interaction confirmed coprecipitation using recombinant epitope-tagged APPextra purified...
Recent studies demonstrate that in addition to its modulatory effect on APP processing, vivo application of Liver X Receptor agonist T0901317 (T0) transgenic and non-transgenic mice decreases the level Aβ42. Moreover, young Tg2576 T0 completely reversed contextual memory deficits. Compared other tissues, regulatory functions LXRs brain remain largely unexplored our knowledge so far is limited cholesterol transporters apoE. In this study we applied APP23 for various times examined gene...
Bexarotene-activated retinoid X receptors (RXRs) ameliorate memory deficits in Alzheimer9s disease mouse models, including mice expressing human apolipoprotein E (APOE) isoforms. The goal of this study was to gain further insight into molecular mechanisms whereby ligand-activated RXR can affect or restore cognitive functions. We used an unbiased approach discover genome-wide changes cistrome (ChIP-Seq) and gene expression profile (RNA-Seq) response bexarotene the cortex APOE4 mice....
The clinical diagnosis of Alzheimer's disease, at its early stage, remains a difficult task. Advanced imaging technologies and laboratory assays to detect Aβ peptides Aβ42 Aβ40, total phosphorylated tau in CSF provide set biomarkers developing AD brain pathology facilitate the diagnostic process. search for biofluid biomarkers, other than CSF, development biomarker have accelerated significantly now represent fastest-growing field research. goal this study was determine differential...
ABCA1, a member of the ATP-binding cassette family transporters, lipidates ApoE (apolipoprotein A) and is essential for generation HDL (high-density lipoprotein)-like particles in CNS (central nervous system). Lack Abca1 increases amyloid deposition several AD (Alzheimer's disease) mouse models. We hypothesized that deletion only one copy APP23 (where APP precursor protein) model mice will aggravate memory deficits these mice. Using Morris Water Maze, we demonstrate 2-year-old heterozygous...