Our laboratory is interested in assessing the contribution of inflammation in the context of Alzheimer’s disease (AD) pathophysiology.  Novel transgenic mice and gene transfer-based methodologies are being employed to experimentally control the expression and/or activity of potent inflammatory cytokines/chemokines due to their purported role(s) in brain inflammation and neurodegeneration. Elucidating the role of inflammation in the AD pathogenic cascade will undoubtedly result in the development of novel diagnostic methodologies and stage-specific therapeutics.  The laboratory’s line of research addresses both the role of inflammation temporally and spatially in pathogenesis as well as examines the interplay between disease-modifying therapies and inflammation to either slow or exacerbate neurodegeneration. 

The laboratory also develops novel vaccines and therapeutics based upon the Herpes simplex virus (HSV) amplicon vector platform for future clinical implementation.  Amplicon vectors are attractive because they may be manipulated to express virtually any combination of genes and possess the largest transgene capacity of any virus vector in current use.  The laboratory continues to refine amplicon-based therapeutics in preclinical disease models. We have recently adapted the amplicon vector platform for efficient and long-term molecular manipulation of neural stem cells during embryogenesis in situ, thus providing a novel and robust means for gene replacement/repair in neurodegenerative diseases arising during early mammalian development.

Janelsins, M.C., M.A. Mastrangelo, K.M. Park, K.L. Sudol, W.C. Narrow, S. Oddo, F.M. LaFerla, H.J. Federoff, and W.J. Bowers.  2008.  Chronic neuronal TNF-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am. J. Path.  In press.

Desai, M.K., K.L. Sudol, M.C. Janelsins, M.A. Mastrangelo, M.E. Frazer, and W.J. Bowers.  2008.  Triple-transgenic Alzheimer’s disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology.  Glia.  In press.

Mastrangelo, M.A. and W.J. Bowers.  2008.  Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer’s disease-related pathologies in male triple-transgenic (3xTg-AD) mice.  BMC Neurosci.  9:81. (doi:10.1186/1471-2202-9-81)

Frazer, M.E., J.E. Hughes, M.A. Mastrangelo, J.L. Tibbens, H.J. Federoff, and W.J. Bowers.  2008.  Reduced pathology and improved behavioral performance in Alzheimer’s disease mice vaccinated with HSV amplicons expressing amyloid-beta and interleukin-4.  Mol. Ther.  16:845-853.

Burris, C.A., S. de Silva, W.C. Narrow, A.E. Casey, L.T. Lotta, Jr., H.J. Federoff, and W.J. Bowers.  2008.  Hexamethylene bisacetamide leads to reduced helper virus-free HSV-1 amplicon expression titers via suppression of ICP0.  J. Gene Med.  10:152-164.

Bowers, W.J. M.C. Janelsins, and H.J. Federoff.  Application to gene therapy and vaccination.  2007.  In: Neuroimmune Pharmacology.  Ed. T. Ikezu and H. Gendelman. Springer, New York, NY. Pg. 709-724 .

Peterson, E.B., M.A. Mastrangelo, H.J. Federoff, and W.J. Bowers.  2007.  Neuronal specificity of HSV/Sleeping Beauty amplicon transduction in utero is driven primarily by tropism and cellular co-factor expression profiles.  Mol. Ther.  15:1848-1855.

Santos, K., D. Simon, E. Conway, W.J. Bowers, S. Mitra, T.H. Foster, A. Lugade, E. Lord, H.J. Federoff, S. Dewhurst, and J.G. Frelinger.  2007.  Spatial and temporal expression of herpes simplex virus type 1 amplicon-encoded genes: implications for their use as immunization vectors.  Hum. Gene Ther.  18:1-13.

Bowers, W.J., M.A. Mastrangelo, H.A. Southerland, D.F. Howard, K.A. Maguire-Zeiss, and H.J. Federoff.  2006.  Neuronal precursor-restricted transduction via in utero CNS gene delivery of a novel bipartite HSV amplicon/transposase hybrid vector.  Mol. Ther.  13:580-588.  Editorial comment 13:457-458.

Bowers, W.J. and H.J. Federoff.  Immunotherapeutic approaches for Alzheimer’s disease.  2006.  In: Gene Therapy for Neurological Disorders.  Ed. P. Lowenstein and M. Castro.  Taylor and Francis, New York, NY.  Pg. 197-227.

Arvanian, V.L., W.J. Bowers, A. Anderson, P.J. Horner, H.J. Federoff, and L.M. Mendell.  2006.  Combined delivery of neurotrophin-3 and NMDA receptors 2D subunit strengthen synaptic transmission in contused and staggered hemisected spinal cord of neonatal rat.  Exp. Neurol.  197:347-352.

Bowers, W.J. and H.J. Federoff.  Herpes simplex virus type 1-derived amplicon vectors.  2006.  In: Gene Transfer: Delivery and Expression of DNA and RNA, A Laboratory Manual.  Ed. J. Rossi and T. Friedmann.  Cold Spring Harbor Press, Cold Spring Harbor, NY.  Pg. 227-254.

Janelsins, M.C., M.A. Mastrangelo, S. Oddo, F.M. LaFerla, H.J. Federoff, and W.J. Bowers.  2005. Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant factor expression specifically within the entorhinal cortex of triple transgenic Alzheimer’s disease mice.  J. Neuroinflammation.  2:23. (doi:10.1186/1742-2094-2-23)

Bowers, W.J., M.A. Mastrangelo, H.A. Stanley, A.E. Casey, L.J. Milo, and H.J. Federoff. 2005.  HSV amplicon-mediated Ab vaccination in Tg2576 mice: Differential antigen-specific immune responses.  Neurobiol. Aging.  26:393-407.

Bowers, W.J. and H.J. Federoff. 2002.  Amyloid immunotherapy-engendered CNS inflammation.  Neurobiol. Aging.  23:675-676.