Keywords:

Alzheimer’s disease, Parkinson’s disease, Neurodegeneration, Aging, Apoptosis, Oxidative stress, Endoplasmic reticulum, Calcium, Protein misfolding, Mitochondria, ß-amyloid, Amyloid plaques, Tau, Neurofibrillary tangles, Cholesterol, Copper, Iron, GSK-3, MAP Kinases, Cdk-5

Education/Training:

• Research Associate then Assistant Professor of Research, Department of Pathology, University of Virginia
• Postdoctoral Fellow, Laval University and University of Quebec, Canada.
• Ph.D., Experimental and Clinical Pharmacology, School of Pharmacy, University Rene Descartes, Paris, France.

Research Interests:

Alzheimer's disease is a devastating neurodegenerative disorder with no known etiology or available cure. This disease is characterized histopathologically by plaques, tangles, and neuronal loss in selected regions of the brain. Plaques consist of aggregates of ß-amyloid (Aß) peptide and tangles are composed of hyperphosphorylated forms of the microtubule-associated protein tau. The role of Aß and tau in the pathogenesis of Alzheimer’s disease, and the mechanisms by which neurons die in the course of this disease, are still a matter of debate.

The broad long-term objectives of my research are to elucidate temporal and spatial relationships between Aß, phosphorylated tau and neuronal death, as well as intracellular mechanisms that control these pathological features. An integral part of my research interests is also to apply strategies for neuroprotection as an initial step in devising therapeutic approaches for the treatment of Alzheimer’s disease.

My research focuses on:

(A) Role of diet and environmental factors in the pathogenesis of Alzheimer’s disease: The majority of Alzheimer’s disease cases are sporadic, without a clear or defined genetic link, suggesting that factors such as the environment or diet may contribute to the etiology of the disease. Emerging data from epidemiological, cell biology and animal studies supports a tight association between dysregulation in cholesterol homeostasis and the pathogenesis of Alzheimer’s disease. However, the extent to which and the mechanisms by which cholesterol may influence the induction or progression of Alzheimer’s disease remain to be determined. Pharmacological manipulation of cholesterol levels and/or effects may offer potential therapeutic benefits if a connection between cholesterol and the pathophysiology of AD can be identified. My research aims to determine functional links between cholesterol imbalance and triggering of Alzheimer’s disease-like pathological features in animal models.

(B) Role of calcium and the endoplasmic reticulum (ER) in underlying neurodegeneration in Alzheimer’s disease: Calcium is essential to neuronal functions, and neuronal survival depends on maintenance of calcium homeostasis. Most of the cellular calcium is stored in the ER, which is also a site where Aß is formed. Impairment of calcium signaling has been suggested to be an early event that precedes the manifestation of Alzheimer’s disease and initiates the accumulation of Aß peptide, which in turn triggers the phosphorylation of tau and cell death. Our working hypothesis is that Aß per se dysregulates calcium homeostasis in the endoplasmic reticulum as an initial step for triggering phosphorylation of tau and causing cell death.

Selected Publications:

• Ghribi O. The role of the endoplasmic reticulum in the accumulation of beta-amyloid peptide in Alzheimer's disease. Curr Mol Med. 2006 Feb;6(1):119-33.
• Ghribi O, Herman MM, Pramoonjago P, Spaulding NK, Savory J. GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases. Neurobiol Dis. 2004;16(2):417-27.
• Ghribi O, Herman MM, Pramoonjago P, Savory J. MPP+ induces the endoplasmic reticulum stress response in rabbit brain involving activation of the ATF-6 and NF-kappaB signaling pathways. J Neuropathol Exp Neurol. 2003;62(11):1144-53.
• Ghribi O, Prammonjago P, Herman MM, Spaulding NK, Savory J. Aß(1-42)-induced JNK and ERK activation in rabbit hippocampus is differentially regulated by lithium but is not involved in the phosphorylation of tau. Mol Brain Res. 2003;119(2):201-6.
• Ghribi O, Herman MM, Savory J. Lithium inhibits Abeta-induced stress in endoplasmic reticulum of rabbit hippocampus but does not prevent oxidative damage and tau phosphorylation. J Neurosci Res. 2003; 71(6):853-62.
• Savory J, Ghribi O, Herman MM. Is amyloid beta-peptide neurotoxic or neuroprotective and what is its role in the binding of metal ions. Neurobiol Aging. 2002;23(6):1089-92.
• Ghribi O, Herman MM, Spaulding NK, Savory J. Lithium inhibits aluminum-induced apoptosis in rabbit hippocampus, by preventing cytochrome c translocation, Bcl-2 decrease, Bax elevation and caspase-3 activation. J Neurochem. 2002;82(1):137-45.
• Ghribi O, Herman MM, Savory J. The endoplasmic reticulum is the main site for caspase-3 activation following aluminum-induced neurotoxicity in rabbit hippocampus. Neurosci Lett. 2002;324(3):217-21.
• Cyr M, Ghribi O, Thibault C, Morissette M, Landry M, Di Paolo T. Ovarian steroids and selective estrogen receptor modulators activity on rat brain NMDA and AMPA receptors. Brain Res Brain Res Rev. 2001;37(1-3):153-61. Review.
• Ghribi O, DeWitt DA, Forbes MS, Arad A, Herman MM, Savory J.Cyclosporin A inhibits Al-induced cytochrome c release from mitochondria in aged rabbits. J Alzheimers Dis. 2001;3(4):387-391.
• Ghribi O, Herman MM, DeWitt DA, Forbes MS, Savory J. Abeta(1-42) and aluminum induce stress in the endoplasmic reticulum in rabbit hippocampus, involving nuclear translocation of gadd 153 and NF-kappaB. Brain Res Mol Brain Res. 2001;96(1-2):30-8.
• Ghribi O, DeWitt DA, Forbes MS, Herman MM, Savory J. Co-involvement of mitochondria and endoplasmic reticulum in regulation of apoptosis: changes in cytochrome c, Bcl-2 and Bax in the hippocampus of aluminum-treated rabbits. Brain Res. 2001;903(1-2):66-73.
• Furling D, Ghribi O, Lahsaini A, Mirault ME, Massicotte G. Impairment of synaptic transmission by transient hypoxia in hippocampal slices: improved recovery in glutathione peroxidase transgenic mice. Proc Natl Acad Sci U S A. 2000;97(8):4351-6.
• Ghribi O, Lapierre L, Girard M, Ohayon M, Nalbantoglu J, Massicotte G. Hypoxia-induced loss of synaptic transmission is exacerbated in hippocampal slices of transgenic mice expressing C-terminal fragments of Alzheimer amyloid precursor protein. Hippocampus. 1999;9(3):201-5.
• Ghribi O, Callebert J, Verrecchia C, Plotkine M, Boulu RG. Blockers of NMDA-operated channels decrease glutamate and aspartate extracellular accumulation in striatum during forebrain ischaemia in rats. Fundam Clin Pharmacol. 1995;9(2):141-6.
• Ghribi O, Callebert J, Plotkine M, Boulu RG. L-NAME modulates glutamate accumulation induced by K(+)-depolarization but not by forebrain ischaemia in the rat striatum. Neurosci Lett. 1994;174(1):34-8.