Room 311, Sanders-Brown Center on Aging
800 South Limestone Street
Lexington, KY 40536-0230
Pathology, Division of Neuropathology
Non-coding RNA in neurodegenerative disease
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. He 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.
A multi-institutional study co-led by Dr. Nelson has defined and established criteria for a new neurological disease called primary age-related tauopathy (PART). Patients with PART develop cognitive impairment that can be indistinguishable from Alzheimer’s disease, but lack amyloid plaques that are a hallmark of AD. Awareness of this neurological disease will help doctors diagnose and develop more effective treatments for patients with different types of memory impairment. In this video clip, Dr. Nelson explains the impetus behind the new diagnosis criteria using asthma and pneumonia as an example of how a general diagnosis (breathing difficulty) might lead to ineffective (or even detrimental) treatment.
We have studied the disease we have termed “HS-Aging”, including multiple (>15) papers with primary data on HS-Aging. HS-Aging is a prevalent, but very under-appreciated (and under-studied!) brain disease that mimics Alzheimer’s disease clinically. We have identified some of the key clinical, pathological, and genetic characteristics of the disease.
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: 20:66-79. 2010. PMCID: PMC2864342 (This study was the first to show an independent correlative contribution of HS-Aging and hippocampal TDP-43 pathology to cognitive impairment, factoring in other pathology-defined comorbidities.)
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. doi: 10.1007/s00401-011-0826. (Here we reported that HS-Aging, like arteriolosclerosis, but unlike Alzheimer’s, is a phenomenon seen most strikingly in the “oldest old”, and highlighted that important contradistinction.)
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. Brain. 2011 May;134(Pt 5):1506-18. doi: 10.1093/brain/awr053. (This was a ground-breaking study of HS-Aging in multiple large autopsy cohorts, and included the first description of a neurocognitive profile that characterizes patients with HS-Aging pathology well before death.)
Nelson PT, Wang WX, Wilfred BR, Wei A, Dimayuga J, Huang Q, Ighodaro E, Artiushin S, Fardo DW. Novel human ABCC9/SUR2 brain-expressed transcripts and an eQTL relevant to hippocampal sclerosis of aging. J Neurochem. 2015 Jun 26. doi: 10.1111/jnc.13202. (Here we showed that the ABCC9 risk alleles are proxies for gene expression regulation, and also identified new transcripts with evidence that the transcripts are differentially regulated by miR-30.)
Our work has been at the cutting edge of digital pathologic studies to quantify pathology with increased rigor and decreased experimental/technical bias:
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.
Attems J, Neltner JH, Nelson PT. Quantitative neuropathological assessment to investigate cerebral multi-morbidity. Alzheimers Res Ther. 2014 Nov 28;6(9):85. doi: 10.1186/s13195-014-0085-y.
Bachstetter AD, Van Eldik LJ, Schmitt FA, Neltner JH, Ighodaro ET, Webster SJ, Patel E, Abner EL, Kryscio RJ, Nelson PT. Disease-related microglia heterogeneity in the hippocampus of Alzheimer's disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol Commun. 2015 May 23;3:32. doi: 10.1186/s40478-015-0209-z.
Neltner JH, Abner EL, Baker S, Schmitt FA, Kryscio RJ, Jicha GA, Smith CD, Hammack E, Kukull WA, Brenowitz WD, Van Eldik LJ, Nelson PT*. Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing. Brain. 2014 Jan;137(Pt 1):255-67. doi: 10.1093/brain/awt318. Epub 2013 Nov 21. (This study incorporated the use of digital pathology-based assessment of cerebrovascular pathology that is directly relevant to the current proposal.)
We participated in multicenter “team science” research efforts, including in the leadership role, and including genetic studies of HS-Aging, that have moved forward the clinical, pathological, and research fields related to cognitive impairment in the elderly.
Nelson PT, Estus S, Abner EL, Parikh I, Malik M, Neltner JH, Ighodaro E, Wang WX, Wilfred BR, Wang LS, Kukull WA, Nandakumar K, Farman ML, Poon WW, Corrada MM, Kawas CH, Cribbs DH, Bennett DA, Schneider JA, Larson EB, Crane PK, Valladares O, Schmitt FA, Kryscio RJ, Jicha GA, Smith CD, Scheff SW, Sonnen JA, Haines JL, Pericak-Vance MA, Mayeux R, Farrer LA, Van Eldik LJ, Horbinski C, Green RC, Gearing M, Poon LW, Kramer PL, Woltjer RL, Montine TJ, Partch AB, Rajic AJ, Richmire K, Monsell SE; Alzheimer’ Disease Genetic Consortium, Schellenberg GD, Fardo DW. ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. Acta Neuropathol. 2014 Jun;127(6):825-43. doi: 10.1007/s00401-014-1282-2. (This was the first GWAS published using HS-Aging as an endophenotype, directly related to the current proposal; we later replicated this result in a separate sample of persons.)
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. doi: 10.1097/NEN.0b013e31825018f7. (This helped to provide consensus about fundamental issues in dementia clinical-pathological correlations, and has been cited >170 times to date.)
Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I, Arnold SE, Attems J, Beach TG, Bigio EH, Cairns NJ, Dickson DW, Gearing M, Grinberg LT, Hof PR, Hyman BT, Jellinger K, Jicha GA, Kovacs GG, Knopman DS, Kofler J, Kukull WA, Mackenzie IR, Masliah E, McKee A, Montine TJ, Murray ME, Neltner JH, Santa-Maria I, Seeley WW, Serrano-Pozo A, Shelanski ML, Stein T, Takao M, Thal DR, Toledo JB, Troncoso JC, Vonsattel JP, White CL 3rd, Wisniewski T, Woltjer RL, Yamada M, Nelson PT*.Primary age-related tauopathy (PART): a common pathology associated with human aging.Acta Neuropathol. 2014 Dec;128(6):755-66. doi: 10.1007/s00401-014-1349-0. Epub 2014 Oct 28.PMID: 25348064(*The PI was senior corresponding author on this paper gathering consensus about a novel pathology-defined disease, which, like HS-Aging, underscores that we still have more complexity to cope with in order to understand the diseases of human brain aging.)
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. PMID: 22265587 . (This is relevant to the current proposal because this consensus document helps define what HS-Aging is, and this group of experts agreed that our citations represent the benchmarks for the field)
We have worked extensively on miRNAs in the human brain (this is a selection from over 30 papers published related to miRNAs in the brain):
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;35(2):335-48.
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. doi: 10.1093/nar/gkr532. Epub 2011 Jun 30. PMID: 21724616
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. PMID: 20678503
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. PMID: 20489155
We analyzed NACC data extensively and productively (>10 papers)
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 Nov;257(11):1875-81. doi: 10.1007/s00415-010-5630-4. Epub 2010 Jun 20. (We started analyzing NACC dataset back in 2010 and showed in this paper that a fundamental demographic parameter, gender, could be highly relevant to neurodegenerative disease mechanisms.)
Brenowitz WD, Monsell SE, Schmitt FA, Kukull WA, Nelson PT*.Hippocampal sclerosis of aging is a key Alzheimer's disease mimic: clinical-pathologic correlations and comparisons with both alzheimer's disease and non-tauopathic frontotemporal lobar degeneration.J Alzheimers Dis. 2014;39(3):691-702. doi: 10.3233/JAD-131880.(This worked help to define clinical and pathological parameters in NACC and how they correlate to HS-Aging pathology.).
Nelson PT, Wang WX, Partch AB, Monsell SE, Valladares O, Ellingson SR, Wilfred BR, Naj AC, Wang LS, Kukull WA, Fardo DW. Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology. J Neuropathol Exp Neurol. 2015 Jan;74(1):75-84. doi: 10.1097/NEN.0000000000000151. (This paper used the power of NACC dataset and genotyping to replicate the ABCC9/HS-Aging association.)
Brenowitz, WD, Nelson PT, Besser LM, Heller KB, Kukull WA.Cerebral amyloid angiopathy and its co-occurrence with Alzheimer's disease and other cerebrovascular neuropathologic changes.Neurobiology of Aging, In Press.(This In Press paper underscores the utility of studying cerebrovascular subtypes in the NACC dataset.)