Lucia Whitman

Publications (16) View all

• Article: Inflammation induced by infection potentiates tau pathological features in transgenic mice.

  Michael Sy, Masashi Kitazawa, Rodrigo Medeiros, Lucia Whitman, David Cheng, Thomas E Lane, Frank M Laferla
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  ABSTRACT: Comorbidities that promote the progression of Alzheimer's disease (AD) remain to be uncovered and evaluated in animal models. Because elderly individuals are vulnerable to viral and bacterial infections, these microbial agents may be considered important comorbidities that could potentiate an already existing and tenuous inflammatory condition in the brain, accelerating cognitive decline, particularly if the cellular and molecular mechanisms can be defined. Researchers have recently demonstrated that triggering inflammation in the brain exacerbates tau pathological characteristics in animal models. Herein, we explore whether inflammation induced via viral infection, compared with inflammation induced via bacterial lipopolysaccharide, modulates AD-like pathological features in the 3xTg-AD mouse model and provide evidence to support the hypothesis that infectious agents may act as a comorbidity for AD. Our study shows that infection-induced acute or chronic inflammation significantly exacerbates tau pathological characteristics, with chronic inflammation leading to impairments in spatial memory. Tau phosphorylation was increased via a glycogen synthase kinase-3β-dependent mechanism, and there was a prominent shift of tau from the detergent-soluble to the detergent-insoluble fraction. During chronic inflammation, we found that inhibiting glycogen synthase kinase-3β activity with lithium reduced tau phosphorylation and the accumulation of insoluble tau and reversed memory impairments. Taken together, infectious agents that trigger central nervous system inflammation may serve as a comorbidity for AD, leading to cognitive impairments by a mechanism that involves exacerbation of tau pathological characteristics.
  American Journal Of Pathology 06/2011; 178(6):2811-22. · 4.89 Impact Factor
• Article: Cell replacement therapies to promote remyelination in a viral model of demyelination.

  Emanuele Tirotta, Kevin S Carbajal, Chris S Schaumburg, Lucia Whitman, Thomas E Lane
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  ABSTRACT: Persistent infection of the central nervous system (CNS) of mice with the neuroadapted JHM strain of mouse hepatitis (MHV) is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS). Although extensive demyelination occurs in mice persistently infected with MHV there is only limited remyelination. Therefore, the MHV model of demyelination is a relevant model for studying disease and evaluating therapeutic approaches to protect cells of the oligodendrocyte lineage and promote remyelination. This concept is further highlighted as the etiology of MS remains enigmatic, but viruses have long been considered as potential triggering agents in initiating and/or maintaining MS symptoms. As such, understanding mechanisms associated with promoting repair within the CNS in the context of a persistent viral infection is critical given the possible viral etiology of MS. This review focuses on recent studies using either mouse neural stem cells (NSCs) or human oligodendrocyte progenitor cells (OPCs) derived from human embryonic stem cell (hESC) to promote remyelination in mice persistently infected with MHV. In addition, the potential role for chemokines in positional migration of transplanted cells is addressed.
  Journal of neuroimmunology 07/2010; 224(1-2):101-7. · 2.84 Impact Factor
• Source

  Available from: Lucia Whitman

  Article: Surgical transplantation of mouse neural stem cells into the spinal cords of mice infected with neurotropic mouse hepatitis virus.

  Kevin S Carbajal, Jason G Weinger, Lucia M Whitman, Chris S Schaumburg, Thomas E Lane
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  ABSTRACT: Mice infected with the neurotropic JHM strain of mouse hepatitis virus (MHV) develop pathological and clinical outcomes similar to patients with the demyelinating disease Multiple Sclerosis (MS). We have shown that transplantation of NSCs into the spinal cords of sick mice results in a significant improvement in both remyelination and in clinical outcome. Cell replacement therapies for the treatment of chronic neurologic diseases are now a reality and in vivo models are vital in understanding the interactions between the engrafted cells and host tissue microenvironment. This presentation provides an adapted method for transplanting cells into the spinal cord of JHMV-infected mice. In brief, we provide a procedure for i) preparation of NSCs prior to transplant, ii) pre-operative care of mice, iii) exposure of the spinal cord via laminectomy, iv) stereotactic injection of NSCs, and iv) post-operative care.
  Journal of Visualized Experiments 01/2011;
• Article: IFN-gamma-mediated suppression of coronavirus replication in glial-committed progenitor cells.

  Lucia Whitman, Haixia Zhou, Stanley Perlman, Thomas E Lane
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  ABSTRACT: The neurotropic JHM strain of mouse hepatitis virus (JHMV) replicates primarily within glial cells following intracranial inoculation of susceptible mice, with relative sparing of neurons. This study demonstrates that glial cells derived from neural progenitor cells are susceptible to JHMV infection and that treatment of infected cells with IFN-gamma inhibits viral replication in a dose-dependent manner. Although type I IFN production is muted in JHMV-infected glial cultures, IFN-beta is produced following IFN-gamma-treatment of JHMV-infected cells. Also, direct treatment of infected glial cultures with recombinant mouse IFN-alpha or IFN-beta inhibits viral replication. IFN-gamma-mediated control of JHMV replication is dampened in glial cultures derived from the neural progenitor cells of type I receptor knock-out mice. These data indicate that JHMV is capable of infecting glial cells generated from neural progenitor cells and that IFN-gamma-mediated control of viral replication is dependent, in part, on type I IFN secretion.
  Virology 01/2009; 384(1):209-15. · 3.35 Impact Factor
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  Available from: Lucia Whitman

  Article: Olig1 function is required for remyelination potential of transplanted neural progenitor cells in a model of viral-induced demyelination.

  Lucia M Whitman, Caroline A Blanc, Chris S Schaumburg, David H Rowitch, Thomas E Lane
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  ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) resulting in cumulative neurologic deficits associated with progressive myelin loss. We have previously shown that transplantation of neural progenitor cells (NPCs) into mice persistently infected with the JHM strain of mouse hepatitis virus (JHMV) results in enhanced differentiation into oligodendrocyte progenitor cells (OPCs) that is associated with remyelination and axonal sparing. The current study examines the contributions of the transcription factor Olig1 on NPC differentiation and remyelination. Under defined conditions, NPCs preferentially differentiate into oligodendroglia whereas NPCs isolated from Olig1-deficient (Olig1-/-) mice exhibit enhanced differentiation into astrocytes. Transplantation of Olig1-/- and Olig1+/+ NPCs into JHMV-infected mice resulted in similar cell survival, proliferation, and selective migration to areas of demyelination. However, only recipients of wild type NPCs exhibited extensive remyelination compared to mice receiving Olig1-/- NPCs. In vivo characterization of NPCs revealed that Olig1+/+ NPCs preferentially differentiated into NG2-positive OPCs and formed processes expressing myelin basic protein that encircled axons. In contrast, the majority of transplanted Olig1-/- NPCs differentiated into GFAP-positive cells consistent with the astrocyte lineage. These results indicate that exogenous NPCs contribute to improved clinical and histological outcome and this is associated with remyelination by this donor population. Further, these findings reveal that Olig1function is required for the remyelination potential of NPCs after transplant, through specification and/or maintenance of oligodendroglial identity.
  Experimental Neurology 03/2012; 235(1):380-7. · 4.70 Impact Factor