Research Topics
Genomes and Genes | William J BowersSummaryAffiliation: University of Rochester Country: USA Publications
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Publications
Ablation of TNF-RI/RII expression in Alzheimer's disease mice leads to an unexpected enhancement of pathology: implications for chronic pan-TNF-α suppressive therapeutic strategies in the brainSara L Montgomery
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY14642, USA
Am J Pathol 179:2053-70. 2011..Overall, our results demonstrate that globally ablated TNF receptor signaling exacerbates pathogenesis and argues against long-term use of pan-anti-TNF-α inhibitors for the treatment of AD...- Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD miceMICHELLE C JANELSINS
Department of Microbiology and Immunology, Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA
Am J Pathol 173:1768-82. 2008..Results presented here suggest that chronic neuronal TNF-alpha expression promotes inflammation and, ultimately, neuronal cell death in this AD mouse model, advocating the development of TNF-alpha-specific agents to subvert AD... - Early oligodendrocyte/myelin pathology in Alzheimer's disease mice constitutes a novel therapeutic targetMaya K Desai
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York, USA
Am J Pathol 177:1422-35. 2010.... - Virion-associated cofactor high-mobility group DNA-binding protein-1 facilitates transposition from the herpes simplex virus/Sleeping Beauty amplicon vector platformSuresh de Silva
Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
Hum Gene Ther 21:1615-22. 2010..As a result, HSV/SB amplicon virions arrive prearmed with HMGB1 protein at levels sufficient for facilitating SB-mediated transposition in the transduced mammalian cell... - Generating differentially targeted amyloid-beta specific intrabodies as a passive vaccination strategy for Alzheimer's diseaseKelly L Sudol
Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York 14642, USA
Mol Ther 17:2031-40. 2009..This approach may provide insights into the functional relevance of intraneuronal A beta accumulation in early AD and potentially lead to the development of new therapeutics... - Triple-transgenic Alzheimer's disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathologyMaya K Desai
Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
Glia 57:54-65. 2009.... - Interferon-{gamma} differentially affects Alzheimer's disease pathologies and induces neurogenesis in triple transgenic-AD miceMichael A Mastrangelo
Center for Neural Development and Disease, University of Rochester Medical Center, NY 14642, USA
Am J Pathol 175:2076-88. 2009..Gaining an understanding as to how these apparently divergent functions are interrelated and controlled could elucidate new therapeutic strategies designed to harness the neuroprotective activity of IFNgamma... - Herpes simplex virus/Sleeping Beauty vector-based embryonic gene transfer using the HSB5 mutant: loss of apparent transposition hyperactivity in vivoSuresh de Silva
Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA
Hum Gene Ther 21:1603-13. 2010.... - Abeta-directed single-chain antibody delivery via a serotype-1 AAV vector improves learning behavior and pathology in Alzheimer's disease miceDeborah A Ryan
Interdepartmental Graduate Program in Neuroscience, University of Rochester Medical Center, Rochester, NY, USA
Mol Ther 18:1471-81. 2010..These results underscore the potential of gene-based passive vaccination for AD, and provide further rationale for the development of Abeta-targeting strategies for this debilitating disease... - Hexamethylene bisacetamide leads to reduced helper virus-free HSV-1 amplicon expression titers via suppression of ICP0Clark A Burris
Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
J Gene Med 10:152-64. 2008.... - An improved method for generating consistent soluble amyloid-beta oligomer preparations for in vitro neurotoxicity studiesDeborah A Ryan
Interdepartmental Graduate Program in Neuroscience, Rochester, NY 14642, USA
J Neurosci Methods 190:171-9. 2010..These synthetic preparations should prove valuable to many studying Abeta-mediated mechanisms underlying AD... - Reduced pathology and improved behavioral performance in Alzheimer's disease mice vaccinated with HSV amplicons expressing amyloid-beta and interleukin-4Maria E Frazer
Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
Mol Ther 16:845-53. 2008..Our study underscores the potential of Abeta immunotherapy for AD and highlights the potency of amplicons in facilitating the immune response modulation to a disease-relevant antigen... - Tumor necrosis factor-alpha potentiates intraneuronal Ca2+ signaling via regulation of the inositol 1,4,5-trisphosphate receptorKEIGAN M PARK
Center for Neural Development and Disease, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York 14642, USA
J Biol Chem 283:33069-79. 2008.... 
Targeting the central nervous system with herpes simplex virus / Sleeping Beauty hybrid amplicon vectorsSuresh de Silva
Department of Neurology, Center for Neural Development and Disease, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642 USA
Curr Gene Ther 11:332-40. 2011..In this review we provide a comprehensive breakdown of the characteristics of the HSV/SB vector system and how it can be efficiently employed in the derivation of CNS-targeted gene therapeutic strategies...- Infectivity of herpes simplex virus type-1 (HSV-1) amplicon vectors in dendritic cells is determined by the helper virus strain used for packagingKathlyn Santos
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 672, Rochester, NY 14642, USA
J Virol Methods 145:37-46. 2007.... - An Alzheimer's disease-relevant presenilin-1 mutation augments amyloid-beta-induced oligodendrocyte dysfunctionMaya K Desai
Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Glia 59:627-40. 2011.... - Effects of herpes simplex virus amplicon transduction on murine dendritic cellsYahui Grace Chiu
Division of Allergy, Immunology, and Rheumatology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
Hum Gene Ther 20:442-52. 2009.... - HSV-1 amplicon vectors elicit polyfunctional T cell responses to HIV-1 Env, and strongly boost responses to an adenovirus primeCindy M P Duke
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
Vaccine 25:7410-21. 2007..This suggests that initial priming can shape immune response quality after a boost. Overall, these findings provide insight into effective vector combinations for HIV-1 vaccine development... - Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer's disease-related pathologies in male triple-transgenic miceMichael A Mastrangelo
Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA
BMC Neurosci 9:81. 2008.... - Neuronal specificity of HSV/sleeping beauty amplicon transduction in utero is driven primarily by tropism and cell type compositionElise B Peterson
Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
Mol Ther 15:1848-55. 2007.... - Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunctionKEIGAN M PARK
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
Cell Signal 22:977-83. 2010..This review will summarize the key events that lead to TNF-alpha elaboration in the CNS, and the effects that these inflammatory signals impart on neuronal signaling in the context of homeostasis and neuropathology... - Impaired TNF-alpha control of IP3R-mediated Ca2+ release in Alzheimer's disease mouse neuronsKEIGAN M PARK
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
Cell Signal 22:519-26. 2010.... - Robust antigen-specific humoral immune responses to sublingually delivered adenoviral vectors encoding HIV-1 Env: association with mucoadhesion and efficient penetration of the sublingual barrierWilliam Domm
Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14627, USA
Vaccine 29:7080-9. 2011..Overall, these findings support the further exploration of the SL delivery route for HIV-1 vaccine delivery... - CD4+ T cell effects on CD8+ T cell location defined using bioluminescenceMitra Azadniv
David H Smith Center for Microbiology and Immunology, Aab Institute for Biomedical Research, University of Rochester Medical Center, Rochester, New York, United States of America
PLoS ONE 6:e16222. 2011..Based on these results, we propose the model that one of the functions of CD4+ T cell "help" is to program the homing potential of CD8+ T cells... - Imaging CD8+ T cell dynamics in vivo using a transgenic luciferase reporterMitra Azadniv
David H Smith Center for Microbiology and Immunology, Aab Institute for Biomedical Research, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA
Int Immunol 19:1165-73. 2007.... - Tumor necrosis factor-alpha-mediated regulation of the inositol 1,4,5-trisphosphate receptor promoterKEIGAN M PARK
Department of Neurology, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York 14642, USA
J Biol Chem 284:27557-66. 2009..Overall, these data delineate a key pathway by which TNF-alpha in a neuronal environment modulates IP(3)R expression and intracellular Ca(2+) homeostasis... - Genetic therapy for the nervous systemWilliam J Bowers
Department of Neurology, Center for Neural Development and Disease, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642, USA
Hum Mol Genet 20:R28-41. 2011..These versatile new tools for manipulation of genetic elements provide the ability to tailor the mode of genetic intervention to specific aspects of a disease state... 
Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous systemSara L Montgomery
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
J Neuroimmune Pharmacol 7:42-59. 2012....- Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's diseaseByoung Dae Lee
Neuroregeneration Program, Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Nat Med 16:998-1000. 2010..These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of Parkinson's disease... - Neuronal precursor-restricted transduction via in utero CNS gene delivery of a novel bipartite HSV amplicon/transposase hybrid vectorWilliam J Bowers
Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 645, Rochester, NY 14642, USA
Mol Ther 13:580-8. 2006.... - Immune shaping and the development of Alzheimer's disease vaccinesHoward J Federoff
Department of Neurology, Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
Sci Aging Knowledge Environ 2005:pe35. 2005.... - Transcriptional and posttranslational regulation of Cre recombinase by RU486 as the basis for an enhanced inducible expression systemStephanos Kyrkanides
Department of Dentistry, Rochester, New York 14620, USA
Mol Ther 8:790-5. 2003.... - Dysfunctional memory CD8+ T cells after priming in the absence of the cell cycle regulator E2F4Simona Bancos
David H Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642USA
Cell Immunol 257:44-54. 2009..These findings demonstrate that the cell cycle repressor E2F4 is essential for the formation of functional memory T cells. A decrease in CD8+ T-lymphocyte compartment would diminish our capacity to control viral infections... - Helper-free HSV-1 amplicons elicit a markedly less robust innate immune response in the CNSJohn A Olschowka
Departments of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
Mol Ther 7:218-27. 2003.... - Spatial and temporal expression of herpes simplex virus type 1 amplicon-encoded genes: implications for their use as immunization vectorsKathlyn Santos
Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA
Hum Gene Ther 18:93-105. 2007..From this and previous work, we conclude that amplicons may engender a potent immune response by directly transducing dendritic cells as well as by cross-priming of antigen produced by other transduced host cells... - HSV amplicons: neuro applicationsCarolyn M Tyler
Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
Curr Gene Ther 6:337-50. 2006..This discourse highlights the successes and challenges encountered using HSV amplicon vectors as tools for the dissection of neural network function and as therapeutics directed against a variety of neurologic disorders... - HSV amplicon-mediated Abeta vaccination in Tg2576 mice: differential antigen-specific immune responsesWilliam J Bowers
Department of Neurology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
Neurobiol Aging 26:393-407. 2005.... - Expression of human immunodeficiency virus type 1 gp120 from herpes simplex virus type 1-derived amplicons results in potent, specific, and durable cellular and humoral immune responsesPeter K Hocknell
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York 14642, USA
J Virol 76:5565-80. 2002..Taken together, these data strongly support the use of helper-free HSV-1 amplicon particles as vaccine delivery vectors... - Measuring the frequency of mouse and human cytotoxic T cells by the Lysispot assay: independent regulation of cytokine secretion and short-term killingJennifer E Snyder
David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, New York, USA
Nat Med 9:231-5. 2003..The simultaneous enumeration of cytokine-secreting and cytotoxic cells should be invaluable for ex vivo analysis of immune responses during infection and autoimmunity... - HSV amplicon-mediated delivery of LIGHT enhances the antigen-presenting capacity of chronic lymphocytic leukemiaKhaled A Tolba
James P Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
Mol Ther 6:455-63. 2002..In aggregate, these data suggest that hf-HSV-LIGHT transduction may be useful for induction of immune responses to CLL and other B-cell lymphoid malignancies... - Cellular immune responses to helper-free HSV-1 amplicon particles encoding HIV-1 gp120 are enhanced by DNA primingXiuqing Wang
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA
Vaccine 21:2288-97. 2003..Collectively, these results demonstrate the utility of HSV amplicon vectors in prime-boost regimens for HIV vaccine development... - p75 neurotrophin receptor protects primary cultures of human neurons against extracellular amyloid beta peptide cytotoxicityYan Zhang
Department of Neurology and Center for Aging and Developmental Biology, University of Rochester, Rochester, New York 14642, USA
J Neurosci 23:7385-94. 2003..Neuroprotection against Abeta is phosphatidylinositide 3-kinase dependent but Akt independent. These results are consistent with a neuroprotective role for p75NTR against extracellular Abeta toxicity in human neurons... - Amyloid immunotherapy-engendered CNS inflammationWilliam J Bowers
Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
Neurobiol Aging 23:675-6; discussion 683-4. 2002 - Neurotrophin-3 transduction attenuates cisplatin spiral ganglion neuron ototoxicity in the cochleaWilliam J Bowers
Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642-8629, USA
Mol Ther 6:12-8. 2002..The potency of NT-3 in SGN neuroprotection suggests that in vivo neurotrophin-based gene therapy is a promising preventative treatment for chemical-induced hearing disorders, and potentially for hearing degeneration due to normal aging... - Reporter gene transfer induces apoptosis in primary cortical neuronsEric R Detrait
Center for Aging and Developmental Biology, Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, New York 14642, USA
Mol Ther 5:723-30. 2002..This work underscores the need for careful design of gene expression constructs. Moreover, in studies where cell injury or toxicity is being evaluated, their use should be carefully considered... - Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue chemokine and CD40L results in augmented antitumor activityKhaled A Tolba
James P Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
Cancer Res 62:6545-51. 2002.... - Somatic mosaic approaches and the aging brainKathleen A Maguire-Zeiss
Department of Neurology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA
Neurobiol Aging 23:977-84. 2002..We will also highlight potential uses for this approach in Alzheimer's disease, a complex pathophysiological state involving changes in many cellular pathways... - Glucocorticoid-regulated VEGF expression in ischemic skeletal muscleIssam A Halaby
Department of Surgery, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
Mol Ther 5:300-6. 2002..This new iteration of VEGF gene delivery provides for fine-tuned angiogenic factor-based therapy for tissues requiring neovascularization... - Effect of promoter strength on protein expression and immunogenicity of an HSV-1 amplicon vector encoding HIV-1 GagKathlyn Santos
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
Vaccine 25:1634-46. 2007..These findings may have implications for the generation of improved HSV-1 amplicon vectors for HIV-1 vaccine delivery... - Adoptively transferred tumor-specific T cells stimulated ex vivo using herpes simplex virus amplicons encoding 4-1BBL persist in the host and show antitumor activity in vivoKyung H Yi
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, and University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA
Cancer Res 67:10027-37. 2007..Tumor-specific T cells stimulated ex vivo using tumor transduced with HSV.4-1BBL expand in vivo following adoptive transfer, resulting in tumor eradication and the generation of tumor-specific CD44+Ly-6C+CD62L- effector memory T cells... - Transfection of tyrosine kinase deleted FGF receptor-1 into rat brain substantia nigra reduces the number of tyrosine hydroxylase expressing neurons and decreases concentration levels of striatal dopamineThomas D Corso
Molecular and Structural Neurobiology and Gene Therapy Program, University at Buffalo, SUNY, Buffalo, NY 14260, USA
Brain Res Mol Brain Res 139:361-6. 2005..Thus, we conclude that reduced FGF signaling in the SN of Parkinsonian patients could play a role in the impaired dopaminergic transmission associated with the degenerative disease... - Effects of ex vivo transduction of mesencephalic reaggregates with bcl-2 on grafted dopamine neuron survivalCaryl E Sortwell
Department of Neurology University of Cincinnati, PO Box 670537, ML0537, Cincinnati, OH 45267 0537, USA
Brain Res 1134:33-44. 2007..Even with highly efficient viral vector-mediated transduction, our results demonstrate that ex vivo gene transfer of bcl-2 to mesencephalic reaggregates is ineffective in increasing grafted DA neuron survival... - Assessment of viral and non-viral gene transfer into adult rat brains using HSV-1, calcium phosphate and PEI-based methodsThomas D Corso
Molecular and Structural Neurobiology and Gene Therapy Program, SUNY, University at Buffalo, Buffalo, NY 14214, USA
Folia Morphol (Warsz) 64:130-44. 2005.... - Combined delivery of neurotrophin-3 and NMDA receptors 2D subunit strengthens synaptic transmission in contused and staggered double hemisected spinal cord of neonatal ratVictor L Arvanian
Department of Neurobiology and Behavior, SUNY at Stony Brook, Life Sciences Building, Stony Brook, NY 11794-5230, USA
Exp Neurol 197:347-52. 2006.... - Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophyAmi Mankodi
Department of Neurology, School of Medicine and Dentistry, University of Rochester, Box 673, 601 Elmwood Avenue, New York 14642, USA
Mol Cell 10:35-44. 2002..We propose that a transdominant effect of mutant RNA on RNA processing leads to chloride channelopathy and membrane hyperexcitability in DM... - Augmentation of anti-tumor responses of adoptively transferred CD8+T cells in the lymphopenic setting by HSV amplicon transductionHovav Nechushtan
Department of Medicine, Miller School of Medicine at the University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA
Cancer Immunol Immunother 57:663-75. 2008.... - Retinal ganglion cell differentiation in cultured mouse retinal explantsSteven W Wang
Department of Biochemistry and Molecular Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA
Methods 28:448-56. 2002.... - Human dendritic cells transduced with herpes simplex virus amplicons encoding human immunodeficiency virus type 1 (HIV-1) gp120 elicit adaptive immune responses from human cells engrafted into NOD/SCID mice and confer partial protection against HIV-1 chalSanthi Gorantla
Center for Neurovirology and Neurodegenerative Disorders, 985880 Nebraska Medical Center, Omaha, NE 68198-5880, USA
J Virol 79:2124-32. 2005..This mouse model may be a useful tool to evaluate human immune responses and protection against viral infection following vaccination... - Viral delivery of NR2D subunits reduces Mg2+ block of NMDA receptor and restores NT-3-induced potentiation of AMPA-kainate responses in maturing rat motoneuronsVictor L Arvanian
Dept. of Neurobiology and Behavior, SUNY at Stony Brook, Life Sciences Bldg. Rm. 550, Stony Brook, NY 11794-5230, USA
J Neurophysiol 92:2394-404. 2004..This approach might be useful for enhancing the function of fibers surviving in the damaged spinal cord... - Herpes simplex virus amplicon delivery of a hypoxia-inducible angiogenic inhibitor blocks capillary formation in hepatocellular carcinomaRichard H Pin
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
J Gastrointest Surg 8:812-22; discussion 822-3. 2004..the control group (P < 0.000001). HSV amplicon-mediated delivery of a hypoxia-inducible soluble VEGF receptor substantially reduces new vessel formation and tumor growth in hepatoma... - Herpes simplex virus amplicon delivery of a hypoxia-inducible soluble vascular endothelial growth factor receptor (sFlk-1) inhibits angiogenesis and tumor growth in pancreatic adenocarcinomaMaura Reinblatt
Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Ann Surg Oncol 12:1025-36. 2005..CONCLUSIONS: HSV amplicon delivery of a hypoxia-inducible soluble VEGF receptor significantly reduces new vessel formation and tumor growth. Tumor hypoxia can thus be used to direct antiangiogenic therapy to pancreatic adenocarcinoma...
Research Grants
- Gene-based TNF-alpha activity modulation in 3xTg-AD miceWilliam Bowers; Fiscal Year: 2007..This work will provide major insight into the involvement of inflammation in the temporal and spatial progression of early AD pathogenic events and may potentially elucidate new therapeutic targets. ..
- Novel Mouse Model to Dissect Alzheimer's Disease PathophysiologyWilliam Bowers; Fiscal Year: 2007..abstract_text> ..
- Gene-based TNF-alpha activity modulation in 3xTg-AD miceWilliam J Bowers; Fiscal Year: 2010..This work will provide major insight into the involvement of inflammation in the temporal and spatial progression of early AD pathogenic events and may potentially elucidate new therapeutic targets. ..