Pathology, Division of Neuropathology
Non-coding RNA in neurodegenerative disease
(left to right) Pete Nelson, James Dimayuga, Bernard R. Wilfred, Wang-Xia Wang, Mary Jennings, Kevin Xie, Willa Huang, Guogen Mao
Work on RNA biology may help point toward strategies to 'un-tangle' the biological questions of Alzheimer's disease, such as why neuritic plaques and neurofibrillary tangles develop in the brains of Alzheimer's patients. (lower left figure shows a low-power photomicrograph depicting miRNA in situ hybridization from human hippocampus; and, at lower right, a medium-power photomicrograph shows human brain stained with a silver impregnation technique to highlight the abnormal and unhealthy-appearing brain microenvironment).
Dr. Pete Nelson is an experimental neuropathologist focusing on Alzheimer’s disease. Dr Nelson is the Director of the Neuropathology Division of the Pathology Department, and he also directs the brain bank and the Neuropathology Core of the University of Kentucky Alzheimer’s Disease Center. Dr. Nelson is responsible for the Alzheimer’s Disease Center brain autopsies. These autopsies are performed with profound respect for the volunteers who are enabling us to help combat this dreadful disease. Dr. Nelson’s career is motivated partly by his own grandmother, Sylvia “Tib” Becker, who died with Alzheimer's disease.
In addition to duties as a neuropathologist, Dr. Nelson is an experimental researcher focusing on the molecular neurochemistry of the human brain — in health and in neurodegenerative disease — particularly in the context of RNA biology. The study of small regulatory RNAs is a relatively new and unexplored research field with much potential. Dr. Nelson's work has focused upon microRNAs (miRNAs). He invented new techniques to analyze and manipulate these small molecules, and studies how miRNA biology is altered in neurodegenerative diseases. Dr. Nelson seeks both to understand how miRNAs contribute to disease pathogenesis, and to explore how specially-designed RNAs may be applied for therapeutic strategies.
For a Powerpoint presentation by Dr. Nelson about exciting new ideas in RNA neurobiology, given for the Alzheimer Research Forum, click the following link. PowerPoint Presentation
Nelson PT*, Smith CD, Abner EL, Wilfred BJ, Wang WX, Neltner JH, Baker M, Fardo DW, Kryscio RJ, Scheff SW, Jicha GA, Jellinger KA, Van Eldik LJ, Schmitt FA. Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease. Acta Neuropathol. 2013 Aug;126(2):161-77.
Nelson PT, Pious NM, Jicha GA, Wilcock DM, Fardo DW, Estus S, Rebeck GW. APOE-E2 and APOE-e4 Correlate With Increased Amyloid Accumulation in Cerebral Vasculature.J Neuropathol Exp Neurol. 2013 Jul;72(7):708-15.
Hébert SS, Wang WX, Zhu Q, Nelson PT*.A Study of Small RNAs from Cerebral Neocortex of Pathology-Verified Alzheimer's Disease, Dementia with Lewy Bodies, Hippocampal Sclerosis, Frontotemporal Lobar Dementia, and Non-Demented Human Controls. J Alzheimers Dis. 2013 Feb 12.
Neltner JH, Abner EL, Schmitt FA, Denison SK, Anderson S, Patel E, Nelson PT. Digital pathology and image analysis for robust high-throughput quantitative assessment of Alzheimer disease neuropathologic changes. J Neuropathol Exp Neurol. 2012 Dec;71(12):1075-85.
Nelson PT*, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, Castellani RJ, Crain BJ, Davies P, Del Tredici K, Duyckaerts C, Frosch MP, Haroutunian V, Hof PR, Hulette CM, Hyman BT, Iwatsubo T, Jellinger KA, Jicha GA, Kövari E, Kukull WA, Leverenz JB, Love S, Mackenzie IR, Mann DM, Masliah E, McKee AC, Montine TJ, Morris JC, Schneider JA, Sonnen JA, Thal DR, Trojanowski JQ, Troncoso JC, Wisniewski T, Woltjer RL, Beach TG. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012 May;71(5):362-81. Review.
Schmitt FA, Nelson PT, Abner E, Scheff S, Jicha GA, Smith C, Cooper G, Mendiondo M, Danner DD, Van Eldik LJ, Caban-Holt A, Lovell MA, Kryscio RJ. University of Kentucky Sanders-Brown healthy brain aging volunteers: donor characteristics, procedures and neuropathology. Curr Alzheimer Res. 2012 Jul 1;9(6):724-33.
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ..National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement. 2012 Jan;8(1):1-13.
Geekiyanage H, Nelson PT, Jicha GA, Chan C, Blood serum miRNA: Non-invasive biomarkers for Alzheimer’s disease. Exp Neurol. 2012 Jun;235(2):491-6.
Hebert, SS, Nelson PT*. Studying microRNAs in the brain: technical lessons learned from the first ten years. Exp Neurol. 2012 Jun;235(2):397-401.
Grondin R, Kaytor M, Ai Y, Nelson PT, Thakker D, Heisel J, Weatherspoon M, Blum J, Burright E, Zhang Z, Kaemmerer W. Six-month Partial Suppression of Huntingtin is Well-tolerated in the Adult Rhesus Brain. Brain. 2012 Apr;135(Pt 4):1197-209.
Stiles D, Zhang Z, Ge P, Nelson B, Grondin R, Ai Y, Hardy P, Nelson PT, Guzaev AP, Butt MT, Charisse K, Kosovrasti V, Tchangov L, Meys M, Maier M, Nechev L, Manoharan M, Kaemmerer WF, Gwost D, Steward GR, Gash DM, Sah DWY. Widespread Suppression of Huntingtin with Convection-Enhanced Delivery of siRNA. Exp Neurol, In Press.
Montine T, Beach T, Bigio E, Cairns N, Dickson DW, Duyckaerts C, Frosch M, Masliah E, Mirra SS, Nelson PT, Phelps A, Schneider JA, Trojanowski JQ, Vinters HV, and Hyman BT. National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathologica. 2011, In Press.
Niedowicz DM, Nelson PT, Murphy MP.Alzheimer’s Disease: Pathological Mechanisms and Recent Insights. Curr Neuropharmacol In Press 2011
Jicha, GA and Nelson, PT. Management of frontotemporal dementia: targeting symptom management in such a heterogeneous disease requires a wide range of therapeutic options. Neurodegen Dis Management, 2011 Apr;1(2):141-156.
Jicha GA, Abner EL, Schmitt FA, Kryscio RJ, Riley KP, Cooper GE, Stiles N, Mendiondo MS, Smith CD, Van Eldik LJ, and Nelson PT*. Preclinical AD Workgroup staging: pathological correlates and potential challenges. Neurobiol Aging 2011 Apr 18. [Epub ahead of print]
Rapoport, SI, Nelson PT. Biomarkers and Evolution in Alzheimer’s disease. Progress in Neurobiol. 2011 Epub Jul 23.
Nelson PT*, Wang WX, Mao G, Wilfred BR, Xie K, Jennings MH, Gao Z, Wang X. Specific sequence determinants of miR-15/107 microRNA gene group targets. Nucleic Acids Res. 2011 Oct;39(18):8163-72..
Nelson PT*, Head E, Schmitt FA, Davis PR, Neltner JH, Jicha GA, Abner EL, Smith CD, Van Eldik LJ, Kryscio RJ, Scheff SW. Alzheimer's disease is not "brain aging": neuropathological, genetic, and epidemiological human studies. Acta Neuropathol. 2011 May; 121(5):571-87.
Nelson, PT*, Schmitt, FA, Lin, Y, Abner, EL, Jicha, GA, Patel, E, Thomason, PC, Neltner, JH, Smith, CD, Santacruz, KS, Sonnen, JA, Poon, LW, Gearing, M, Green, RC, Woodard, JL, Van Eldik, LJ, Kryscio, RJ, Hippocampal sclerosis in advanced age: clinical and pathological features in 106 cases Brain, 2011 May;134(5):1506-18.
Wang WX, Huang Q, Hu Y, Stromberg AJ, Nelson PT*. Patterns of microRNA expression in normal and early Alzheimer's disease human temporal cortex: white matter versus gray matter. Acta Neuropathol. 2010 Oct 10.
Wang WX, Kyprianou N, Wang X, Nelson PT*. Dysregulation of the mitogen granulin in human cancer through the miR-15/107 microRNA gene group. Cancer Res. 2010 70(22):9137-42.
Finnerty JR, Wang WX, Hébert SS, Wilfred BR, Mao G, Nelson PT*. The miR-15/107 group of microRNA genes: evolutionary biology, cellular functions, and roles in human diseases. J Mol Biol. 2010 Sep 24;402(3):491-509.
Nelson PT*, Schmitt FA, Jicha GA, Kryscio RJ, Abner EL, Smith CD, Van Eldik LJ, Markesbery WR. Association between male gender and cortical Lewy body pathology in large autopsy series. J Neurol. 2010
Wang WX, Wilfred BR, Madathil SK, Tang G, Hu Y, Dimayuga J, Stromberg AJ, Huang Q, Saatman KE, Nelson PT*. miR-107 regulates granulin/progranulin with implications for traumatic brain injury and neurodegenerative disease. Am J Pathol. 2010 Jul;177(1):334-45.
Wang WX, Wilfred BR, Xie K, Jennings MH, Hu Y, Stromberg AJ, Nelson PT*. Individual microRNAs (miRNAs) display distinct mRNA targeting "rules" RNA Biol. 2010 May 5;7(3).
Nelson PT*, Kukull WA, Frosch MP. Thinking outside the box: Alzheimer-type neuropathology that does not map directly onto current consensus recommendations. JNEN. 2010 May;69(5):449-54
Nelson PT*, Wang WX. MiR-107 is Reduced in Alzheimer's Disease Brain Neocortex: Validation Study. J Alzheimers Dis. 2010
Nelson PT*, Kiriakidou M, Mourelatos Z, Tan GS, Jennings MH, Xie K, Wang WX. High-throughput experimental studies to identify miRNA targets directly, with special focus on the mammalian brain. Brain Res. 2010 Jun 18;1338:122-30.
Nelson PT*, Dimayuga J, Wilfred, BR, MicroRNA in situ hybridization in the human entorhinal and transentorhinal cortex. Front Hum Neurosci, 2010
Wang W-X, Wilfred BR, Hu Y, Stromberg AJ, Nelson PT*, Argonaute co-immunoprecipitation with RIP-CHIP show that miRNA transfection alter global patterns of mRNA recruitment to microribonucleoprotein complexes. RNA, 2010.
Nelson PT*, Jicha GA, Kryscio RJ, Abner EL, Schmitt FA, Cooper G, Xu LO, Smith CD, Markesbery WR. Low sensitivity in clinical diagnoses of dementia with Lewy bodies. J Neurol. 2009 Oct 1.
Nelson, PT*, Kryscio, RJ, Jicha, GA, Abner, EL, Schmitt, FA, Xu, L, Cooper, G, Smith, CD, Markesbery, WR, Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies, Neurology (2009)
Nelson, PT*, Kryscio, RJ, Jicha, GA, Abner, EL, Schmitt, FA, Xu, L, Cooper, G, Smith, CD, Markesbery, WR, Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer disease. J Neuropathol Exp Neurol. 2009 Jul;68(7):774-84
Nelson PT*, Abner, EA, Scheff, SW, Schmitt, FA, Kryscio, RJ, Jicha, GA, Smith, CD, Patel, E, Markesbery, WR, Alzheimer pathology in the precuneus is not increased relative to other areas of neocortex across a range of cognitive impairment. Neurosci Letters, 2009.
Nelson PT*, Braak H, and Markesbery WR, Neuropathology and Cognitive Impairment in Alzheimer’s Disease: A Complex but Coherent Relationship. J Neuropathol Exp Neurol. 2009 Jan;68(1):1-14.
Nelson PT*, Abner, EA, Schmitt, FA, Kryscio, RJ, Jicha, GA, Smith, CD, Davis, DG, Poduska, JW, Patel, E, Mendiondo, MS, Markesbery, WR, Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons. Brain Pathol, (In Press).
Nelson PT*, Smith, CD, Abner, EA, Schmitt, FA, Scheff, SW, Davis, GD, Keller, JN, Jicha, GA, Davis, D, Wang, W-X, Hartman, A, Katz, DG, and Markesbery WR, Human cerebral neuropathology of Type 2 diabetes mellitus. BBA-Mol Basis of Disease, 2008
Nelson PT*, Kryscio, RJ, Abner, EA, Schmitt, FA, Jicha, GA, Mendiondo, MS, Cooper, G, Smith, CB, and Markesbery, WR, Acetylcholinesterase inhibitor treatment is associated with relatively slow cognitive decline in patients with Alzheimer’s disease and AD+DLB. J Alzheim Dis, 2008
Nelson PT*, Wang WX, Wilfred BR, Tang G. Technical variables in high-throughput miRNA expression profiling: Much work remains to be done. Biochim Biophys Acta. 2008 Apr 7.