Craig S. Atwood, PhD

Portrait of Craig S. Atwood, PhD
Associate Professor
Medicine
Address: 
D4219 GRECC 11G VAMC
2500 Overlook Terrace
Madison, WI 53792
Telephone: 
(608) 256-1901 x11664
Focus Groups: 
Neuroscience/Neuropathology
Signal Transduction
Education: 
PhD, Biochemistry, The University of Western Australia
Research Summary: 
Aging; endocrinology; development; degenerative diseases of the central nervous system
Research Detail: 

Dr. Atwood has diverse research interests based around the "Reproductive-Cell Cycle Theory of Aging" (Bowen and Atwood, 2004; Atwood and Bowen, 2011). This theory introduces a new definition of aging that has facilitated the conceptualization of why and how we age at the evolutionary, physiological and molecular levels. The basic premise behind the research is that hormones that regulate reproduction in mammals act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence. In essence, this theory proposes that reproductive hormones regulate our aging by modulating the life cycle of cells. Importantly, the theory is not simply a philosophical work; it has immediate and practical implications for extending longevity and delaying/preventing age-related diseases.

Below are some of the different research themes ongoing in the laboratory.

  1. Endocrine Dyscrasia and Alzheimer’s Disease. The aging theory evolved from research conducted on how the age-related dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause and during andropause promotes neurodegeneration. From these studies we found that one member of this axis, the gonadotropin luteinizing hormone (LH) which becomes elevated in serum with aging and which accumulates in pyramidal neurons in the AD brain (Bowen et al., 2002), alters amyloid-β precursor (AβPP) protein processing and increases amyloid-ß generation (Bowen et al., 2004), the major component of amyloid plaques that deposit in the brains of individuals with AD. Our and other research has confirmed this finding in a transgenic mouse model of AD, and additionally demonstrated that GnRH analogues can stabilize cognition (Casadesus et al., 2006; Lin et al., 2010). Moreover, neurons in the senescent brain develop other phenotypic characteristics of dividing/transformed cells, such as the expression of LH and osteopontin (Wilson et al., 2006; Wung et al., 2007). We have determined that the endocrine dyscrasia associated with aging also decreases the selective permeability of the blood-brain barrier, which may be a precursor to cerebrovascular diseases including stroke (Wilson et al., 2008). From these basic research observations and insights came the basis for the aging theory. Aside from my own research findings, strong support for the theory was recently published by another group in which they show that high levels of a second gonadotropin, follicle-stimulating hormone (FSH), promote osteoporosis, independent of low estrogen levels (Sun et al., 2006), i.e. FSH, and not estrogens are primarily responsible for osteoporosis. These 2 independent lines of evidence (LH/amyloid production and FSH/osteoclast proliferation) suggest that the surge in gonadotropins following menopause and with andropause is the driving force behind senescent changes seen in aging humans. This research is providing a major paradigm shift in our understanding of age-related diseases.
  2. Hormonal Regulation of Aging and Reproduction. A second line of research is aimed at defining the exact mechanisms by which reproduction and reproductive hormones regulate aging. In this respect, we recently identified a GnRH receptor orthologue in Caenorhabditis elegans, a model of longevity studies (Vadakkadath Meethal et al., 2006). This is the first report of an evolutionarily conserved GnRH receptor in C. elegans, a central component of the endocrine system that orchestrates reproduction. The identification of an evolutionarily conserved GnRH receptor opens the way to using C. elegans as a model system to study reproductive endocrinology and it’s affect on longevity.
  3. Autocrine/Paracrine Mechanisms of LH and Neurosteroid Production in the Brain. We have identified in the brain a ‘mini-HPG’ axis that regulates the synthesis of neurosteroids (Wilson et al., 2006; Liu et al., 2008; Vadakkadath Meethal et al., 2009). The identification of paracrine/autocrine mechanisms in the brain, linked with endocrine mechanisms, for the control of sex hormone synthesis and signaling is important for our understanding of the neuroendocrinology of aging and age-related diseases.
  4. Amyloid Biology. A fourth line of research in my laboratory developed during the last decade has resulted in important discoveries regarding the neurochemical factors that promote the deposition of the amyloid-β protein. This work includes identification of the copper binding sites of amyloid-β both in vivo (Dong et al., 2003) and how this metal ion interaction leads to the oxidative modification of the protein (Atwood et al., 2004). In related studies, we have shown the metal ion chelator/antioxidant, alpha-lipoic acid, stabilizes cognition in a mouse model of AD (Atwood et al., unpublished data), and in collaborative studies (Drs. Veurink and Martins) have demonstrated that the use of combination antioxidant therapies can reverse neurodegeneration in an animal model of protein deposition (Veurink et al., 2002), suggesting a novel antioxidant therapy for AD. Another line of research related to the function of amyloid focuses on the long-standing and very interesting question of whether amyloid-β is neurotoxic or neurotrophic. Since joining UW, we have demonstrated that amyloid-β is both; neurotrophic to undifferentiated neurons, but toxic to differentiated neurons via a Cdk5 dependent tau phosphorylation pathway (Liu et al., 2004). In addition, we have found that amyloid-β production is increased only when neurons commit to death (Verdile et al., in preparation). Further, the physiochemical properties of amyloid-β indicate it to be a novel vascular sealant that can seal vascular lesions without compromising blood supply to the brain (Atwood et al., 2002a, b; 2003). Thus, amyloid-β may have as a normal physiological function the repair and growth of neurons during times of neuronal restructuring, i.e. during development, following injury and during senescence.
  5. Hormonal Regulation of Embryogenesis. Using human embryonic stem cells as a model system for early human embryonic development, we have demonstrated that the pregnancy hormones progesterone and hCG have obligatory developmental functions during embryogenesis (Gallego et al., 2008, 2010). hCG signals hESC to divide and differentiate into an embryoid body, and subsequently into a neuroectodermal rosette. Differentiation of hESC into neural precursor cells is mediated by the upregulation of steroidogenesis by hCG signaling through the luteinizing hormone/hCG receptor. Although hCG and progestagens are often considered primarily reproductive hormones with maternal influences, it is now clear that paracrine/juxtacrine signaling of hCG (and opioids) for mobilization of cholesterol for progesterone production by the epiblast/ synctiotrophoblast following conception is essential for human blastulation and neurulation. This paracrine/juxtacrine signaling by extraembryonic tissues is the commencement of trophic support by placental tissues in the growth and development of the human embryo.
Selected Publications: 
Putative Gonadotropin Releasing Hormone Agonist Therapy and Dementia: An Application of Medicare Hospitalization Claims Data. Smith MA, Bowen RL, Nguyen RQ, Perry G, Atwood CS, Rimm AA. J Alzheimers Dis. 2018 May 16. doi: 10.3233/JAD-170847. [Epub ahead of print] PMID: 29782310
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle BW, Boland A, Raybould R, Bis JC, Martin ER, Grenier-Boley B, Heilmann-Heimbach S, Chouraki V, Kuzma AB, Sleegers K, Vronskaya M, Ruiz A, Graham RR, Olaso R, Hoffmann P, Grove ML, Vardarajan BN, Hiltunen M, Nöthen MM, White CC, Hamilton-Nelson KL, Epelbaum J, Maier W, Choi SH, Beecham GW, Dulary C, Herms S, Smith AV, Funk CC, Derbois C, Forstner AJ, Ahmad S, Li H, Bacq D, Harold D, Satizabal CL, Valladares O, Squassina A, Thomas R, Brody JA, Qu L, Sánchez-Juan P, Morgan T, Wolters FJ, Zhao Y, Garcia FS,Denning N, Fornage M, Malamon J, Naranjo MCD, Majounie E, Mosley TH, Dombroski B, Wallon D, Lupton MK, Dupuis J, Whitehead P, Fratiglioni L, Medway C, Jian X, Mukherjee S, Keller L, Brown K, Lin H, Cantwell LB, Panza F, McGuinness B, Moreno-Grau S, Burgess JD, Solfrizzi V, Proitsi P, Adams HH, Allen M, Seripa D, Pastor P, Cupples LA, Price ND, Hannequin D, Frank-García A, Levy D, Chakrabarty P, Caffarra P, Giegling I, Beiser AS, Giedraitis V, Hampel H, Garcia ME, Wang X, Lannfelt L, Mecocci P, EiriksdottirG, Crane PK, Pasquier F, Boccardi V, Henández I, Barber RC, Scherer M, Tarraga L, Adams PM, Leber M, Chen Y, Albert MS, Riedel-Heller S, Emilsson V, Beekly D, Braae A, Schmidt R, Blacker D, Masullo C, Schmidt H, Doody RS, Spalletta G, Longstreth WT Jr, Fairchild TJ, Bossù P, Lopez OL, Frosch MP, Sacchinelli E, Ghetti B, Yang Q, Huebinger RM, Jessen F, Li S, Kamboh MI, Morris J, Sotolongo-Grau O, Katz MJ, Corcoran C, Dunstan M, Braddel A, Thomas C, Meggy A, Marshall R, Gerrish A, Chapman J, Aguilar M, Taylor S, Hill M, Fairén MD, Hodges A, Vellas B, Soininen H, Kloszewska I, Daniilidou M, Uphill J, Patel Y, Hughes JT, Lord J, Turton J, Hartmann AM, Cecchetti R, Fenoglio C, Serpente M, Arcaro M, Caltagirone C, Orfei MD, Ciaramella A, Pichler S, Mayhaus M, Gu W, Lleó A, Fortea J, Blesa R, Barber IS, Brookes K, Cupidi C, Maletta RG, Carrell D, Sorbi S, Moebus S, Urbano M, Pilotto A, Kornhuber J, Bosco P, Todd S, Craig D, Johnston J, Gill M, Lawlor B, Lynch A, Fox NC, Hardy J; ARUK Consortium, Albin RL, Apostolova LG, Arnold SE, Asthana S, Atwood CS, Baldwin CT, Barnes LL, Barral S, Beach TG, Becker JT, Bigio EH, Bird TD, Boeve BF, Bowen JD, Boxer A, Burke JR, Burns JM, Buxbaum JD, Cairns NJ, Cao C, Carlson CS, Carlsson CM, Carney RM, Carrasquillo MM, Carroll SL, Diaz CC, Chui HC, Clark DG, Cribbs DH, Crocco EA, DeCarli C, Dick M, Duara R, Evans DA, Faber KM, Fallon KB, Fardo DW, Farlow MR, Ferris S, Foroud TM, Galasko DR, Gearing M, Geschwind DH, Gilbert JR, Graff-Radford NR, Green RC, Growdon JH, Hamilton RL, Harrell LE, Honig LS, Huentelman MJ, Hulette CM, Hyman BT, Jarvik GP, Abner E, Jin LW, Jun G, Karydas A, Kaye JA, Kim R, Kowall NW, Kramer JH, LaFerla FM, Lah JJ, Leverenz JB, Levey AI, Li G, Lieberman AP, Lunetta KL, Lyketsos CG, Marson DC, Martiniuk F, MashDC, Masliah E, McCormick WC, McCurry SM, McDavid AN, McKee AC, Mesulam M, Miller BL, Miller CA, Miller JW, Morris JC, Murrell JR, Myers AJ, O'Bryant S, Olichney JM, Pankratz VS, Parisi JE, Paulson HL, Perry W, Peskind E, Pierce A, Poon WW, Potter H, QuinnJF, Raj A, Raskind M, Reisberg B, Reitz C, Ringman JM, Roberson ED, Rogaeva E, Rosen HJ, Rosenberg RN, Sager MA, Saykin AJ, Schneider JA, Schneider LS, Seeley WW, Smith AG, Sonnen JA, Spina S, Stern RA, Swerdlow RH, Tanzi RE, Thornton-Wells TA, Trojanowski JQ, Troncoso JC, Van Deerlin VM, Van Eldik LJ, Vinters HV, Vonsattel JP, Weintraub S, Welsh-Bohmer KA, Wilhelmsen KC, Williamson J, Wingo TS, Woltjer RL, Wright CB, Yu CE, Yu L, Garzia F, Golamaully F, Septier G, Engelborghs S, Vandenberghe R, De Deyn PP, Fernadez CM, Benito YA, Thonberg H, Forsell C, Lilius L, Kinhult-Stählbom A, Kilander L, Brundin R, Concari L, Helisalmi S, Koivisto AM, Haapasalo A, Dermecourt V, Fievet N, Hanon O, Dufouil C, Brice A, Ritchie K, Dubois B, Himali JJ, Keene CD, Tschanz J, Fitzpatrick AL, Kukull WA, Norton M, Aspelund T, Larson EB, Munger R, Rotter JI, Lipton RB, Bullido MJ, Hofman A, Montine TJ, Coto E, Boerwinkle E, Petersen RC, Alvarez V, Rivadeneira F, Reiman EM, Gallo M, O'Donnell CJ, Reisch JS, Bruni AC, Royall DR, Dichgans M, Sano M, Galimberti D, St George-Hyslop P, Scarpini E, Tsuang DW, Mancuso M, Bonuccelli U, Winslow AR, Daniele A, Wu CK; GERAD/PERADES, CHARGE, ADGC, EADI, Peters O, Nacmias B, Riemenschneider M, Heun R, Brayne C, Rubinsztein DC, Bras J, Guerreiro R, Al-Chalabi A, Shaw CE, Collinge J, Mann D, Tsolaki M, Clarimón J, Sussams R, Lovestone S, O'Donovan MC, Owen MJ, Behrens TW, Mead S, Goate AM, Uitterlinden AG, Holmes C, Cruchaga C, Ingelsson M, Bennett DA, Powell J, Golde TE, Graff C, De Jager PL, Morgan K, Ertekin-Taner N, Combarros O, Psaty BM, Passmore P, Younkin SG, Berr C, Gudnason V, Rujescu D, Dickson DW, Dartigues JF, DeStefano AL, Ortega-Cubero S, Hakonarson H, Campion D, Boada M, Kauwe JK, Farrer LA, Van Broeckhoven C, Ikram MA, Jones L, Haines JL, Tzourio C, Launer LJ, Escott-Price V, Mayeux R, Deleuze JF, Amin N, Holmans PA, Pericak-Vance MA, Amouyel P, van Duijn CM, Ramirez A, Wang LS, Lambert JC, Seshadri S, Williams J, Schellenberg GD. Nat Genet. 2017 Sep;49(9):1373-1384. doi: 10.1038/ng.3916. Epub 2017 Jul 17. PMID: 28714976
Does the degree of endocrine dyscrasia post-reproduction dictate post-reproductive lifespan? Lessons from semelparous and iteroparous species. Atwood CS, Hayashi K, Meethal SV, Gonzales T, Bowen RL. Geroscience. 2017Feb;39(1):103-116. doi: 10.1007/s11357-016-9955-5. Epub 2017 Mar 7. PMID: 28271270
Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Jun GR, Chung J, Mez J, Barber R, Beecham GW, Bennett DA, Buxbaum JD, Byrd GS, Carrasquillo MM, Crane PK, Cruchaga C, De Jager P, Ertekin-Taner N, Evans D, Fallin MD, Foroud TM, Friedland RP, Goate AM, Graff-Radford NR, Hendrie H, Hall KS, Hamilton-Nelson KL, Inzelberg R, Kamboh MI, Kauwe JSK, Kukull WA, Kunkle BW, Kuwano R, Larson EB, Logue MW, Manly JJ, Martin ER, Montine TJ, Mukherjee S, Naj A, Reiman EM, Reitz C, Sherva R, St George-Hyslop PH, Thornton T, Younkin SG, Vardarajan BN, Wang LS, Wendlund JR, Winslow AR; Alzheimer's Disease Genetics Consortium, Haines J, Mayeux R, Pericak-Vance MA, Schellenberg G, Lunetta KL, Farrer LA. Alzheimers Dement. 2017 Jul;13(7):727-738. doi: 10.1016/j.jalz.2016.12.012. Epub 2017 Feb 7. PMID: 28183528
Conjugated Linoleic Acid Administration Induces Amnesia in Male Sprague Dawley Rats and Exacerbates Recovery from Functional Deficits Induced by a Controlled Cortical Impact Injury. Geddes RI, Hayashi K, Bongers Q, Wehber M, Anderson IM, Jansen AD, Nier C, Fares E, Farquhar G, Kapoor A, Ziegler TE, VadakkadathMeethal S, Bird IM, Atwood CS. PLoS One. 2017 Jan 26;12(1):e0169494. doi: 10.1371/journal.pone.0169494. eCollection 2017. Erratum in: PLoS One. 2017 Nov 21;12 (11):e0188611. PMID: 28125600
Myocardial infarction in the Wisconsin Longitudinal Study: the interaction among environmental, health, social, behavioural and genetic factors. Gonzales TK, Yonker JA, Chang V, Roan CL, Herd P, Atwood CS. BMJ Open. 2017 Jan 23;7(1):e011529. doi: 10.1136/bmjopen-2016-011529. PMID: 28115328
Not All Androgen Deprivation Therapies Are Created Equal: Leuprolide and the Decreased Risk ofDeveloping Alzheimer's Disease. Bowen RL, Butler T, Atwood CS. J Clin Oncol. 2016 Aug 10;34(23):2800. doi: 10.1200/JCO.2015.66.3997. Epub 2016 Jun 13. No abstract available. PMID: 27298416
Insulin Resistance is Associated with Increased Levels of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Reduced Memory Function in At-Risk Healthy Middle-Aged Adults. Hoscheidt SM, Starks EJ, Oh JM, Zetterberg H, Blennow K, Krause RA, Gleason CE, Puglielli L, Atwood CS, Carlsson CM, Asthana S, Johnson SC, Bendlin BB. J Alzheimers Dis. 2016 Apr 12;52(4):1373-83. doi: 10.3233/JAD-160110. PMID: 27079723
The spatiotemporal hormonal orchestration of human folliculogenesis, early embryogenesis and blastocyst implantation. Atwood CS, Vadakkadath Meethal S. Mol Cell Endocrinol. 2016 Jul 15;430:33-48. doi: 10.1016/j.mce.2016.03.039. Epub 2016 Apr 1. Review. PMID: 27045358
Assessment of the genetic variance of late-onset Alzheimer's disease. Ridge PG, Hoyt KB, Boehme K, Mukherjee S, Crane PK, Haines JL, Mayeux R, Farrer LA, Pericak-Vance MA, Schellenberg GD, Kauwe JSK; Alzheimer's Disease Genetics Consortium (ADGC). Neurobiol Aging. 2016 May;41:200.e13-200.e20. doi: 10.1016/j.neurobiolaging.2016.02.024. Epub 2016 Mar 3. PMID: 27036079