A5074353247- Alzheimer's disease research and treatments
- Neuroscience and Neuropharmacology Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Neurogenesis and neuroplasticity mechanisms
- Prion Diseases and Protein Misfolding
- Nerve injury and regeneration
- Cholinesterase and Neurodegenerative Diseases
- Cellular transport and secretion
- Computational Drug Discovery Methods
- Receptor Mechanisms and Signaling
- Ion channel regulation and function
- Neurological diseases and metabolism
- Trace Elements in Health
- Neuropeptides and Animal Physiology
- Neurotransmitter Receptor Influence on Behavior
- Tryptophan and brain disorders
- Nuclear Receptors and Signaling
- Pain Mechanisms and Treatments
- Pharmacological Effects and Toxicity Studies
- Biochemical and Structural Characterization
- Fatty Acid Research and Health
- Memory and Neural Mechanisms
- HIV-related health complications and treatments
- Pharmacological Receptor Mechanisms and Effects
- Genetic Neurodegenerative Diseases
University of Toronto
2011-2025
Occupational Cancer Research Centre
2006-2025
Canada Research Chairs
2011
Institute of Medical Biology
2006
Czech Academy of Sciences, Institute of Physiology
2006
Toronto Western Hospital
2002-2003
University Health Network
2002-2003
New York University
2002
Hospital for Sick Children
2002
SickKids Foundation
2002
Although neurotrophins have traditionally been regarded as neuronal survival factors, recent work has suggested a role for these factors in synaptic plasticity. In particular, brain-derived neurotrophic factor (BDNF) rapidly enhances transmission hippocampal neurons through trkB receptor stimulation and postsynaptic phosphorylation mechanisms. Activation of also modulates long-term potentiation, which N -methyl- d -aspartate glutamate receptors play key role. However, the final common...
A fundamental objective of anesthesia research is to identify the receptors and brain regions that mediate various behavioral components anesthetic state, including amnesia, immobility, unconsciousness. Using complementary in vivo vitro approaches, we found GABAA contain alpha5 subunit (alpha5GABAARs) play a critical role amnesia caused by prototypic intravenous etomidate. Whole-cell recordings from hippocampal pyramidal neurons showed etomidate markedly increased tonic inhibitory...
Downregulation of brain-derived neurotrophic factor (BDNF) in the cortex occurs early progression Alzheimer's disease (AD). Since BDNF plays a critical role neuronal survival, synaptic plasticity, and memory, reduction may contribute to cellular loss memory deficits characteristic AD. In vitro evidence suggests that amyloid-beta (A beta) contributes downregulation AD, but specific A beta aggregation state responsible for this vivo is unknown. present study, we examined cortical levels mRNA...
Abstract Docosahexaenoic acid (22:6n‐3) is the major brain n‐3 polyunsaturated fatty and it possible that docosahexaenoic anti‐inflammatory in as known to be other tissues. Using a combination of models including fat‐1 transgenic mouse, chronic dietary modulation wild‐type mice, acute direct infusion, we demonstrated unesterified attenuates neuroinflammation initiated by intracerebroventricular lipopolysaccharide. Hippocampal was assessed gene expression immunohistochemistry. Furthermore,...
Glial cell line-derived neurotrophic factor (GDNF) promotes survival of midbrain dopaminergic neurons and motoneurons. Expression GDNF mRNA in cerebellum raises the possibility that cells within this structure might also respond to GDNF. To examine potential trophic activities GDNF, dissociated cultures gestational day 18 rat were grown for < or = 21 days presence factor. increased Purkinje number without affecting overall glial cells. A maximal response (50% above control) was elicited...
Nicastrin is an integral component of the high molecular weight presenilin complexes that control proteolytic processing amyloid precursor protein and Notch. We report here nicastrin most probably a type 1 transmembrane glycoprotein expressed at moderate levels in brain cultured neurons. Immunofluorescence studies demonstrate localized endoplasmic reticulum, Golgi, discrete population vesicles. Glycosidase analyses reveal endogenous undergoes conventional, trafficking-dependent maturation...
APH-1 and PEN-2 genes modulate the function of nicastrin presenilins in <i>Caenorhabditis elegans</i>. Preliminary studies transfected mammalian cells overexpressing tagged proteins suggest that this genetic interaction is mediated by a direct physical interaction. Using protein encoded on human chromosome 1 (APH-1<sub>1</sub>L; also known as APH-1a) an archetype, we report here endogenous forms are predominantly expressed intracellular membrane compartments, including endoplasmic reticulum...
The GTF2IRD1 general transcription factor is a candidate for involvement in the varied cognitive and neurobehavioral symptoms of microdeletion disorder, Williams–Beuren syndrome (WBS). We show that mice with heterozygous or homozygous disruption Gtf2ird1 exhibit decreased fear aggression increased social behaviors. These findings are reminiscent hypersociability diminished strangers hallmarks WBS. Other core features WBS, such as anxiety problems spatial learning were not present targeted...
Neurotrophins have long been thought to act as target-derived factors that regulate the survival and differentiation of afferent neurons. Recently, brain-derived neurotrophic factor (BDNF) was shown elicit rapid increases in synaptic activity cultured hippocampal neurons by enhancing responsiveness excitatory input. These findings suggest a postsynaptic localization neurotrophin receptors. In this study, we examined expression trkB, high-affinity receptor for BDNF, density (PSD),...
The presenilin 1 (PS1) and 2 (PS2) proteins are necessary for proteolytic cleavage of the amyloid precursor protein (APP) within its transmembrane domain. One these events (termed γ-secretase) generates C-terminal end Aβ-peptide by proteolysis near residue 710 or 712 APP<sub>770</sub>. Another event γ-like ε-secretase cleavage) cleaves 721 at ∼2–5 residues inside cytoplasmic membrane boundary to generate a series stable, APP fragments. This latter is analogous S3-cleavage Notch. We report...
The brain cannot synthesize n-6 or n-3 PUFAs de novo and requires their transport from the blood. Two models of fatty acid uptake have been proposed. One passive diffusion unesterified acids through endothelial cells blood-brain barrier, other lipoproteins via a lipoprotein receptor on luminal membrane cells. This study tested whether low density (LDLr) is necessary for maintaining PUFA concentrations. Because cortex has basal expression LDLr anterior stem relatively high expression, we...
Cerebral malaria (CM) is associated with a high mortality rate, and long-term neurocognitive impairment in approximately one third of survivors. Adjunctive therapies that modify the pathophysiological processes involved CM may improve outcome over anti-malarial therapy alone. PPARγ agonists have been reported to immunomodulatory effects variety disease models. Here we report adjunctive improved survival outcomes Plasmodium berghei ANKA experimental model CM. Compared alone, administered mice...
Presenilin 1 (PS1) mutations are responsible for a majority of early onset familial Alzheimer's disease (FAD) cases, in part by increasing the production Aβ peptides. However, emerging evidence suggests other possible effects PS1 on synaptic dysfunction where might contribute to pathology independent Aβ. We chose study L286V mutation, an aggressive FAD mutation which has never been analyzed at electrophysiological and morphological levels. In addition, we first time long term wild-type human...
The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies Africa are at risk malaria pregnancy (MIP) however the impact exposure to MIP on fetal is unknown. Complement activation, particular C5a, may contribute neuropathology adverse outcomes during MIP. We used an experimental model standardized neurocognitive testing, MRI, micro-CT HPLC analysis neurotransmitter levels, test hypothesis that alters through a C5a-C5aR...
Abstract Polyglucosans are glycogen molecules with overlong chains, which hyperphosphorylated in the neurodegenerative Lafora disease (LD). Brain polyglucosan bodies (PBs) cause fatal diseases including and adult body (ABPD), for treatments, biomarkers, good understanding of their pathogenesis currently missing. Mutations genes phosphatase laforin or E3 ubiquitin ligase malin can LD. By depleting PTG, an activator chain-elongating enzyme synthase (GYS1), laforin- malin-deficient LD mice, we...
Absence of functional presenilin 1 (PS1) protein leads to loss gamma-secretase cleavage the amyloid precursor (betaAPP), resulting in a dramatic reduction beta peptide (Abeta) production and accumulation alpha- or beta-secretase-cleaved COOH-terminal fragments betaAPP (alpha- beta-CTFs). The major fragment (CTF) brain was identified as betaAPP-CTF-(11-98), which is consistent with observation that cultured neurons generate primarily Abeta-(11-40). In PS1(-/-) murine fibroblasts expressing...