A5038895570- Alzheimer's disease research and treatments
- Cholesterol and Lipid Metabolism
- Drug Transport and Resistance Mechanisms
- Retinal Imaging and Analysis
- Glaucoma and retinal disorders
- Peroxisome Proliferator-Activated Receptors
- Amyotrophic Lateral Sclerosis Research
- Dementia and Cognitive Impairment Research
- Advanced Neuroimaging Techniques and Applications
- Retinal Diseases and Treatments
- Retinal Development and Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Traumatic Brain Injury and Neurovascular Disturbances
- Cardiac Arrest and Resuscitation
- Traumatic Brain Injury Research
- RNA Research and Splicing
- Nuclear Receptors and Signaling
- Parkinson's Disease Mechanisms and Treatments
- Prion Diseases and Protein Misfolding
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Intracerebral and Subarachnoid Hemorrhage Research
- Mechanical Circulatory Support Devices
- Medical Imaging and Analysis
- Spinal Cord Injury Research
- Genomic variations and chromosomal abnormalities
University of British Columbia
2016-2025
Vancouver General Hospital
2017-2025
International Collaboration On Repair Discoveries
2021-2024
Geisinger Health System
2018
Vancouver Coastal Health
2017
Child and Family Research Institute
2006-2010
University of British Columbia Hospital
2009
University of Bonn
2008
ABCA1 is a cholesterol transporter that widely expressed throughout the body. Outside central nervous system (CNS), functions in biogenesis of high-density lipoprotein (HDL), where it mediates efflux and phospholipids to apolipoprotein (apo) A-I. Deficiency results lack circulating HDL greatly reduced levels apoA-I. also cells within CNS, but its roles brain lipid metabolism are not yet fully understood. In brain, glia synthesize apolipoproteins involved CNS metabolism. Here we demonstrate...
APOE genotype is a major genetic risk factor for late-onset Alzheimer disease (AD). ABCA1, member of the ATP-binding cassette family active transporters, lipidates apoE in CNS. Abca1–/– mice have decreased lipid associated with and increased amyloid deposition several AD mouse models. We hypothesized that overexpressing ABCA1 brain would lipidation apoE-containing lipoproteins deposition. To address these hypotheses, we created PrP-mAbca1 Tg overexpress Abca1 throughout under control prion...
Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer disease (AD). It has been hypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes neurons. However, regulation cholesterol supply neurons apoE-containing high density lipoproteins remains to be clarified. We show for first time brain-specific metabolite produced by neurons, i.e. 24(S)-hydroxycholesterol, induces transcription,...
ABCA1, a cholesterol transporter expressed in the brain, has been shown recently to be required maintain normal apoE levels and lipidation central nervous system. In addition, ABCA1 reported modulate β-amyloid (Aβ) production vitro. These observations raise possibility that may play role pathogenesis of Alzheimer disease. Here we report deficiency does not affect soluble or guanidine-extractable Aβ Tg-SwDI/B amyloid precursor protein/presenilin 1 (APP/PS1) mice, but rather is associated with...
The cholesterol transporter ATP-binding cassette A1 (ABCA1) moves lipids onto apolipoproteins including apolipoprotein E (apoE), which is the major carrier in brain and an established genetic risk factor for late-onset Alzheimer disease (AD). In amyloid mouse models of AD, ABCA1 deficiency exacerbates amyloidogenesis, whereas overexpression ameliorates load, suggesting a role Aβ metabolism. Agonists liver X receptors (LXR), GW3965, induce transcription several genes apoE, reduce levels...
The expression of the cholesterol transporter ATP-binding cassette A1 (ABCA1) in brain and its role lipidation apolipoproteins indicate that ABCA1 may play a critical metabolism. To investigate homeostasis trafficking, we characterized mice specifically lacked CNS, generated using Cre/loxP recombination system. These showed reduced plasma high-density lipoprotein (HDL) levels associated with decreased content enhanced uptake esterified from HDL. Increased HDL receptor SR-BI capillaries...
Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for 60-70% all dementias. AD often under-diagnosed and recognized only at a later, more advanced stage, this delay in diagnosis has been suggested as contributing factor numerous unsuccessful treatment trials. Although there no known cure AD, early important management care. A hallmark deposition amyloid-β (Aβ)-containing senile neuritic plaques neurofibrillary tangles composed hyperphosporylated tau brain. However,...
Rationale: Secondary brain hypoxia portends significant mortality in ischemic diseases; yet, our understanding of hypoxic injury (HIBI) pathophysiology humans remains rudimentary. Objective: To quantify the impact secondary on to neurovascular unit patients with HIBI. Methods and Results: We conducted a prospective interventional study invasive neuromonitoring 18 post–cardiac arrest The partial pressures tissue O 2 (PbtO ) intracranial pressure were directly measured via intraparenchymal...
Abstract Amyloid beta (Aβ) deposits in the retina of Alzheimer’s disease (AD) eye may provide a useful diagnostic biomarker for AD. This study focused on relationship Aβ with macroglia and microglia, as these glial cells are hypothesized to play important roles homeostasis clearance AD retina. Significantly higher load was found compared controls, specifically mid-peripheral region. showed significantly less immunoreactivity against fibrillary acidic protein (GFAP) glutamine synthetase (GS)...
The liver X receptor/retinoid receptor (LXR/RXR)-regulated gene ABCA1 effluxes cellular cholesterol and phospholipid to apolipoprotein A1 (apoA1), which is the rate-limiting step in high-density lipoprotein synthesis. RXR pathway plays a critical role testicular lipid trafficking, RXRbeta-deficient male mice are sterile accumulate lipids Sertoli cells. Here, we demonstrate that mRNA protein abundant cells, whereas germ cells express little ABCA1. LXR/RXR agonists stimulate expression...
Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases TIA1 mutations, together comparisons sporadic ALS (sALS) due repeat expansions C9orf72 (C9orf72+). All patients confirmed mutations female. The phenotype was heterogeneous a range age at onset from late twenties...
Abstract Background Central nervous system (CNS) injury following initiation of veno-venous extracorporeal membrane oxygenation (VV-ECMO) is common. An acute decrease in partial pressure arterial carbon dioxide (PaCO 2 ) VV-ECMO has been suggested as an etiological factor, but the challenges diagnosing CNS injuries made discerning a relationship between PaCO and difficult. Methods We conducted prospective cohort study adult patients undergoing for respiratory failure. Arterial blood gas...
Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological cognitive phenotypes in AD mouse models. The transporter ABCG1 LXR-responsive highly expressed brain. In vitro, conflicting reports exist as to whether promotes or impedes Aβ production. To clarify the vivo roles metabolism brain we assessed outcome...
Lipid trafficking in the brain is essential for maintenance and repair of neuronal membranes, especially after neurotoxic insults. However, lipid metabolism not completely understood. In plasma, LCAT catalyses esterification free cholesterol on circulating lipoproteins, a key step maturation HDL. Brain lipoproteins are apolipoprotein E (apoE)-containing, HDL-like particles secreted initially as lipid-poor discs by glial cells. synthesized within brain, suggesting that it may play role these...
The purpose of this study was to evaluate the effects whole body overexpression human ABCG1 on atherosclerosis in apoE(-/-) mice.We generated BAC transgenic mice which is expressed from endogenous regulatory signals, leading a 3- 7-fold increase protein across various tissues. Although transgene rescued lung lipid accumulation ABCG1(-/-) mice, it did not affect plasma levels, macrophage cholesterol efflux HDL, atherosclerotic lesion area or levels tissue cholesterol, ester, phospholipids,...
Abstract Introduction Patients with Alzheimer's disease (AD) and dementia Lewy bodies (DLB) frequently demonstrate coexistent AD neuropathological change (ADNC) body pathology (LBP) at autopsy. We investigated the effects of ADNC LBP on clinical presentation these patients. Methods retrospectively compared pathological features patients different severity LBP. also burden medullary between without autonomic dysfunction. Results Compared to pure ADNC, AD/LBP have higher prevalence DLB...
Although intracellular cholesterol levels are known to influence the proteolysis of beta-amyloid precursor protein (APP), effect specific genes that regulate metabolism on APP processing remains poorly understood. The transporter ABCG1 facilitates efflux HDL and is expressed in brain. Notably, human gene maps chromosome 21q22.3, individuals with Down syndrome (DS) typically manifest Alzheimer's disease (AD) neuropathology their 30s. Here, we demonstrate expression enhances amyloid-beta...
Mutations in the TANK binding kinase 1 gene (TBK1) are associated with amyotrophic lateral sclerosis and/or frontotemporal dementia; however, range of clinical phenotypes and neuropathological changes these mutations have not yet been completely elucidated. We present detailed clinical, neuroimaging, features two brothers carrying TBK1 p.Gly272_Thr331del mutation. Both presented very similar unusual including primary progressive aphasia asymmetric-onset (PLS). Repeated electrophysiological...
Lipid transport in the brain is coordinated by glial-derived lipoproteins that contain apolipoprotein E (apoE) as their primary protein. Here we show apoE secreted from wild-type (WT) murine mixed glia nascent lipoprotein subspecies ranging 7.5 to 17 nm diameter. Negative-staining electron microscropy (EM) revealed rouleaux, suggesting a discoidal structure. Potassium bromide (KBr) density gradient ultracentrifugation showed all subspecies, except an 8.1 particle, were lipidated. Glia...