Christian Pike, PhD

Professor of Gerontology, Assistant Dean of Research

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Overview

Research in my lab is broadly focused on Alzheimer’s disease (AD), with the general goals of elucidating factors that regulate AD pathogenesis and pursuing translational approaches that will be useful in the prevention and/or treatment of the disease. Our approach to investigating research questions involves the use of complementary cellular, biochemical and molecular techniques to analyze relationships in human tissues, wild-type and transgenic rodent models, and cultured cells.

A primary area of focus in my laboratory is the relationship between age-related loss of steroid hormones and the development of AD. For example, our research with postmortem human brain has helped to identify testosterone loss in aging men as a risk factor for AD. In rodent models, we observe that depletion of androgens accelerates development of AD-like neuropathology and increases neuronal vulnerability to toxic insult. Cell culture studies continue to identify the relevant underlying mechanisms for these androgen effects, including investigation of classic genomic actions (e.g., regulation of genes such as neprilysin) as well as activation of rapid cell signaling pathways (e.g., MAPK/ERK, CREB, PKC). In ongoing translational studies, we are building upon our basic science advances to develop specific therapeutic interventions that selectively activate protective androgen pathways (e.g., synthetic testosterone mimetics). Using this general research strategy, we are pursuing conceptually parallel basic science and translational projects to evaluate the interactions between estrogen and progesterone actions in the regulation of neurodegenerative cascades associated with AD.

A new area of research in the lab seeks to understand the relationships between obesity, type 2 diabetes, and AD. Recent epidemiological findings have identified obesity in middle age, and its downstream consequences metabolic syndrome and type 2 diabetes, as significant risk factors for the development of AD in old age. Our efforts are focused at understanding the mechanistic links between these conditions, including the interactive roles of adiposity, neuroinflammation, and age-related changes in testosterone and estrogen.

Awards

  • Alzheimer’s Association: Turken Award, 2000

Publications

  • Apolipoprotein E polymorphisms and female fertility in a transgenic mouse model of Alzheimer’s disease Sci Rep. 2024 Jul 10; 14(1):15873. . View in PubMed
  • Microglial TLR4 Mediates White Matter Injury in a Combined Model of Diesel Exhaust Exposure and Cerebral Hypoperfusion Stroke. 2024 Apr; 55(4):1090-1093. . View in PubMed
  • Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology Aging Cell. 2024 Mar 22; e14153. . View in PubMed
  • Protection against APOE4 -associated aging phenotypes with the longevity-promoting intervention 17a-estradiol in male mice bioRxiv. 2024 Mar 14. . View in PubMed
  • Microglia/macrophage-specific deletion of TLR-4 protects against neural effects of diet-induced obesity bioRxiv. 2024 Feb 14. . View in PubMed
  • Alzheimer’s disease ferroptotic associations with oxidative damage and neuronal loss bioRxiv. 2023 Sep 19. . View in PubMed
  • Effects of APOE Genotype and Western Diet on Metabolic Phenotypes in Female Mice Metabolites. 2023 Feb 16; 13(2). . View in PubMed
  • Role of estrogen in women’s Alzheimer’s disease risk as modified by APOE J Neuroendocrinol. 2023 02; 35(2):e13209. . View in PubMed
  • Androgens Regulate Tau Phosphorylation Through Phosphatidylinositol 3-Kinase-Protein Kinase B-Glycogen Synthase Kinase 3ß Signaling Neuroscience. 2022 Jun 29. . View in PubMed
  • Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer’s models Cell Rep. 2022 09 27; 40(13):111417. . View in PubMed
  • Microglial transcription profiles in mouse and human are driven by APOE4 and sex iScience. 2021 Nov 19; 24(11):103238. . View in PubMed
  • Second to fourth digit ratio (2D:4D) is associated with dementia in women Early Hum Dev. 2020 10; 149:105152. . View in PubMed
  • Dementia risk in women higher in same-sex than opposite-sex twins Alzheimers Dement (Amst). 2020; 12(1):e12049. . View in PubMed
  • Staining and Quantification of ß-Amyloid Pathology in Transgenic Mouse Models of Alzheimer’s Disease Methods Mol Biol. 2020; 2144:211-221. . View in PubMed
  • Aging Reduces Estradiol Protection Against Neural but Not Metabolic Effects of Obesity in Female 3xTg-AD Mice Front Aging Neurosci. 2020; 12:113. . View in PubMed
  • APOE genotype affects metabolic and Alzheimer-related outcomes induced by Western diet in female EFAD mice FASEB J. 2019 03; 33(3):4054-4066. . View in PubMed
  • Effects of aging, high-fat diet, and testosterone treatment on neural and metabolic outcomes in male brown Norway rats Neurobiol Aging. 2019 01; 73:145-160. . View in PubMed
  • TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity J Neuroinflammation. 2018 Nov 05; 15(1):306. . View in PubMed
  • Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans Sci Rep. 2018 09 21; 8(1):14212. . View in PubMed
  • TSPO ligand PK11195 improves Alzheimer-related outcomes in aged female 3xTg-AD mice Neurosci Lett. 2018 09 14; 683:7-12. . View in PubMed
  • Obesity Accelerates Alzheimer-Related Pathology in APOE4 but not APOE3 Mice eNeuro. 2017 May-Jun; 4(3). . View in PubMed
  • The Oxygen Paradox, the French Paradox, and age-related diseases Geroscience. 2017 12; 39(5-6):499-550. . View in PubMed
  • Age-dependent regulation of obesity and Alzheimer-related outcomes by hormone therapy in female 3xTg-AD mice PLoS One. 2017; 12(6):e0178490. . View in PubMed
  • Sex and the development of Alzheimer’s disease J Neurosci Res. 2017 01 02; 95(1-2):671-680. . View in PubMed
  • Obesity and sex interact in the regulation of Alzheimer’s disease Neurosci Biobehav Rev. 2016 Aug; 67:102-18. . View in PubMed
  • Interactions between inflammation, sex steroids, and Alzheimer’s disease risk factors Front Neuroendocrinol. 2016 10; 43:60-82. . View in PubMed
  • The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer’s disease of humans and mice Neurobiol Aging. 2016 Jan; 37:47-57. . View in PubMed
  • The perimenopausal aging transition in the female rat brain: decline in bioenergetic systems and synaptic plasticity Neurobiol Aging. 2015 Jul; 36(7):2282-2295. . View in PubMed
  • Impact of continuous versus discontinuous progesterone on estradiol regulation of neuron viability and sprouting after entorhinal cortex lesion in female rats Endocrinology. 2015 Mar; 156(3):1091-9. . View in PubMed
  • Menopause, obesity and inflammation: interactive risk factors for Alzheimer’s disease Front Aging Neurosci. 2015; 7:130. . View in PubMed
  • Diet-induced obesity and low testosterone increase neuroinflammation and impair neural function J Neuroinflammation. 2014 Sep 16; 11:162. . View in PubMed
  • Selective androgen receptor modulator RAD140 is neuroprotective in cultured neurons and kainate-lesioned male rats Endocrinology. 2014 Apr; 155(4):1398-406. . View in PubMed
  • Alzheimer’s disease and type 2 diabetes: multiple mechanisms contribute to interactions Curr Diab Rep. 2014 Apr; 14(4):476. . View in PubMed
  • Differential effects of synthetic progestagens on neuron survival and estrogen neuroprotection in cultured neurons Mol Cell Endocrinol. 2014 Mar 25; 384(1-2):52-60. . View in PubMed
  • Ligand for translocator protein reverses pathology in a mouse model of Alzheimer’s disease J Neurosci. 2013 May 15; 33(20):8891-7. . View in PubMed
  • Age-related changes in neuroactive steroid levels in 3xTg-AD mice Neurobiol Aging. 2013 Apr; 34(4):1080-9. . View in PubMed
  • Gender, sex steroid hormones, and Alzheimer’s disease Horm Behav. 2013 Feb; 63(2):301-7. . View in PubMed
  • Sex-specific effects of high fat diet on indices of metabolic syndrome in 3xTg-AD mice: implications for Alzheimer’s disease PLoS One. 2013; 8(10):e78554. . View in PubMed
  • 17ß-estradiol and progesterone regulate expression of ß-amyloid clearance factors in primary neuron cultures and female rat brain Endocrinology. 2012 Nov; 153(11):5467-79. . View in PubMed
  • Evaluation of the effects of testosterone and luteinizing hormone on regulation of ß-amyloid in male 3xTg-AD mice Brain Res. 2012 Jul 23; 1466:137-45. . View in PubMed
  • Caspase activation contributes to astrogliosis Brain Res. 2012 Apr 23; 1450:102-15. . View in PubMed
  • Sex hormones, aging, and Alzheimer’s disease Front Biosci (Elite Ed). 2012 01 01; 4(3):976-97. . View in PubMed
  • Continuous versus cyclic progesterone exposure differentially regulates hippocampal gene expression and functional profiles PLoS One. 2012; 7(2):e31267. . View in PubMed
  • Brain levels of sex steroid hormones in men and women during normal aging and in Alzheimer’s disease Neurobiol Aging. 2011 Apr; 32(4):604-13. . View in PubMed
  • Sex differences in ß-amyloid accumulation in 3xTg-AD mice: role of neonatal sex steroid hormone exposure Brain Res. 2010 Dec 17; 1366:233-45. . View in PubMed
  • Progesterone inhibits estrogen-mediated neuroprotection against excitotoxicity by down-regulating estrogen receptor-ß J Neurochem. 2010 Dec; 115(5):1277-87. . View in PubMed
  • Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogen and androgen pathways Brain Res. 2010 Nov 04; 1359:281-90. . View in PubMed
  • Continuous and cyclic progesterone differentially interact with estradiol in the regulation of Alzheimer-like pathology in female 3xTransgenic-Alzheimer’s disease mice Endocrinology. 2010 Jun; 151(6):2713-22. . View in PubMed
  • Age-related changes in serum and brain levels of androgens in male Brown Norway rats Neuroreport. 2009 Nov 25; 20(17):1534-7. . View in PubMed
  • Dihydrotestosterone activates CREB signaling in cultured hippocampal neurons Brain Res. 2009 Nov 17; 1298:1-12. . View in PubMed
  • Protective actions of sex steroid hormones in Alzheimer’s disease Front Neuroendocrinol. 2009 Jul; 30(2):239-58. . View in PubMed
  • Progesterone blocks estrogen neuroprotection from kainate in middle-aged female rats Neurosci Lett. 2008 Nov 21; 445(3):229-32. . View in PubMed
  • Androgens regulate neprilysin expression: role in reducing beta-amyloid levels J Neurochem. 2008 Jun 01; 105(6):2477-88. . View in PubMed
  • Progesterone receptors: form and function in brain Front Neuroendocrinol. 2008 May; 29(2):313-39. . View in PubMed
  • Androgen cell signaling pathways involved in neuroprotective actions Horm Behav. 2008 May; 53(5):693-705. . View in PubMed
  • Selective estrogen receptor modulators differentially regulate Alzheimer-like changes in female 3xTg-AD mice Endocrinology. 2008 May; 149(5):2607-11. . View in PubMed
  • Androgen regulation of beta-amyloid protein and the risk of Alzheimer’s disease Brain Res Rev. 2008 Mar; 57(2):444-53. . View in PubMed
  • Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice J Neurosci. 2007 Nov 28; 27(48):13357-65. . View in PubMed
  • Flutamide and cyproterone acetate exert agonist effects: induction of androgen receptor-dependent neuroprotection Endocrinology. 2007 Jun; 148(6):2936-43. . View in PubMed
  • Estrogen regulates Bcl-w and Bim expression: role in protection against beta-amyloid peptide-induced neuronal death J Neurosci. 2007 Feb 07; 27(6):1422-33. . View in PubMed
  • Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer’s disease J Neurosci. 2006 Dec 20; 26(51):13384-9. . View in PubMed
  • Progestins inhibit the neuroprotective effects of estrogen in rat hippocampus Brain Res. 2006 Jul 12; 1099(1):206-10. . View in PubMed
  • Androgens, aging, and Alzheimer’s disease Endocrine. 2006 Apr; 29(2):233-41. . View in PubMed
  • Conventional protein kinase C isoforms mediate neuroprotection induced by phorbol ester and estrogen J Neurochem. 2006 Jan; 96(1):204-17. . View in PubMed
  • Androgens activate mitogen-activated protein kinase signaling: role in neuroprotection J Neurochem. 2005 Sep; 94(6):1639-51. . View in PubMed
  • The synthetic estrogen 4-estren-3 alpha,17 beta-diol (estren) induces estrogen-like neuroprotection Neurobiol Dis. 2005 Jun-Jul; 19(1-2):331-9. . View in PubMed
  • Neuroprotective properties of selective estrogen receptor agonists in cultured neurons Brain Res. 2005 May 31; 1045(1-2):217-23. . View in PubMed
  • Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w J Neurosci. 2005 Feb 02; 25(5):1149-58. . View in PubMed
  • Age-related testosterone depletion and the development of Alzheimer disease JAMA. 2004 Sep 22; 292(12):1431-2. . View in PubMed
  • Exercise increases the vulnerability of rat hippocampal neurons to kainate lesion Brain Res. 2003 May 09; 971(2):239-44. . View in PubMed
  • Estrogen activates protein kinase C in neurons: role in neuroprotection J Neurochem. 2003 Mar; 84(6):1340-8. . View in PubMed
  • The influence of the carboxyl terminus of the Alzheimer Abeta peptide on its conformation, aggregation, and neurotoxic properties Neuromolecular Med. 2002; 1(1):81-94. . View in PubMed
  • Testosterone attenuates beta-amyloid toxicity in cultured hippocampal neurons Brain Res. 2001 Nov 16; 919(1):160-5. . View in PubMed