Gary E. Landreth, Ph.D.
Professor, Anatomy & Cell Biology
B.A., University of Kansas (1972)
Ph.D., University of Michigan (1977)
Postdoctoral Training, Stanford University (1977-1980)
The biology of neuroinflammation in Alzheimer’s disease.
The AD brain is typified by a robust inflammatory response mediated ‘activated’ plaque-associated microglia and this response is postulated to contribute to cognitive impairment and ultimately neuronal death. We were amongst the first to identify the receptors for fibrillar forms of Ab. We identified an ensemble of receptors, including scavenger receptors, TLRs and their coreceptors which act in concert to bind amyloid fibrils and initiate microglial responses through multiple parallel signal transduction pathways. We have subsequently validated their involvement by genetic inactivation of the fAb receptors and signaling elements. Significantly, we have recently reported that the plaque associated macrophages are not resident microglia, but derive from blood borne monocytes that invade the AD brain and specifically associate with plaques and mediate the proinflammatory response that typifies the disease. The laboratory is currently working to understand the diverse nature of the inflammatory response and how it might simultaneously exacerbate or ameliorate the various aspects of the disease.
Roles of Nuclear Receptors in CNS disorders.
Nuclear receptors are ligand-activated transcription factors that act broadly to regulate metabolism as well as myeloid cell phenotype. We were the first to document the efficacy of agonists of these receptors in CNS disorders, most prominently Alzheimer’s disease. We demonstrated that nuclear receptor agonists improved AD-related phenotypes and improved learning and memory in animal models of disease. The work catalyzed a large number of studies, both in my laboratory and by others, in various animal models of CNS disorders. Importantly, we have translated this work into clinical trials of PPARg and RXR agonists in AD, and there are now several phase II and phase III trials of nuclear receptor agonists underway in several CNS disorders. We are currenty investigating new drug candidates that target these receptors.
Roles of apolipoprotein E in Alzheimer’s disease pathogenesis.
One of the principal unanswered questions in Alzheimer’s disease pathogenesis is how a variant of the apolipoprotein E gene, ApoE4, confers dramatically elevated risk for the disease. We found that ApoE acts physiologically to promote the proteolytic degradation of ApoE, and the ApoE4 isoform is impaired in this function. Importantly, induction of ApoE expression by PPARg or RXR agonists resulted in enhanced clearance of soluble forms of Ab that was accompanied by improved neural network function and reversal of cognitive deficits in mouse models of AD. ApoE is also involved in a number of other disease related processes and the laboratory is interested in elucidating its multiple roles in AD pathogenesis.
The neurobiology of the ERK MAP kinases.
My laboratory is investigating roles the ERK MAP kinases play in the development of structures derived from the neural crest, as well as the telencephalon and cerebellum. The recognition of roles of the ERKs in CNS development led to investigation of their roles in corticogenesis in animals in which the ERKs were knocked out in neural progenitors. The ERKs where they were found to regulate neurogenesis through regulation of cell cycle dynamics. Indeed, mutations of the upstream elements of the ERK MAP kinase pathways lead to a number of Neuro cranio-facial syndromes or ‘Ras-opathies’. A recently described microdeletion of 16p11.2 associated with autism includes the ERK1 gene. We established that a syngenic mouse model exhibited phenotypes perturbation of corticogenesis and impaired behavior, consistent with inactivation of ERK1. Our current work is focused on establishing the actions of the ERKs in animal models of autism and experimental therapeutics to attenuate their behavioral deficits.
Publication since 2015:
Seaberg B, Henslee G, Wang S, Paez-Colasante X, Landreth GE, Rimer M. Muscle-derived ERK1/2 MAP kinases are required for the maintenance of adult myofibers and their neuromuscular junctions. Mol Cell Biol. 35: 1238-1253, 2015. PMID25605336
Malm T, Mariani M, Donovan LJ, Neilson L, Landreth GE. Activation of the nuclear receptor PPARd is neuroprotective in a transgenic mouse model of Alzheimer’s disease through inhibition of inflammation. J Neuroinflammation. 12:1-7, 2015. PMID 25592770
Pucilowska, J., Vithayathil, J., Tavares, E., Kelly, C., Karlo J. and Landreth, G. The 16p11.2 Deletion Mouse Model of Autism Exhibits Altered Cortical Progenitor Proliferation and Brain Cytoarchitecture Linked to the ERK MAPK Pathway. J. Neurosci. 35:3190-3200, 2015.
Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, Xu G, Margevicius D, Karlo JC, Sousa GL, Cotleur AC, Butovsky O, Bekris L, Staugaitis SM, Leverenz JB, Pimplikar SW, Landreth GE, Howell GR, Ransohoff RM, Lamb BT. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer 's disease mouse models. J Exp Med. 212:287-295, 2015 PMID: 25732305
Savage, JC, Jay, T., Goduni, E., Quigley, C., Mariani, M., Malm, T., Ransohoff, R., Lamb, BT and Landreth, GE. Nuclear receptors license phagocytosis in TREM2+ myleloid cells in mouse models of Alzheimer’s disease. J. Neurosci. 35:6532-6543, 2015.PMID 25904803
Vithaytahil, J., Pucilowska, J., Goodnough,, LH., Atit, R. and GE Landreth. . Dentate gyrus development requires ERK activity to maintain progenitor population and MAPK pathway feedback regulation. J. Neurosci. 35:6836-6848, 2015 PMID: 25926459.
Casali, B., Corona, A., Mariaqni, M., Karlo, J, Ghosal, K and GE Landreth. Omega-3 fatty acids augment the actions of nuclear receptor agonists in a mouse model of Alzheimer’s disease. J. Neurosci. 35:9173-9181, 2015. PMID: 26085639
Corona AW, Kodoma N, Casali BT, Landreth GE. ABCA1 is Necessary for Bexarotene-Mediated Clearance of Soluble Amyloid Beta from the Hippocampus of APP/PS1 Mice. J Neuroimmune Pharmacol. 2015 Jul 15. PMID: 26175148
Skerrett R, Pellegrino MP, Casali BT, Taraboanta L, Landreth GE. Combined Liver X Receptor/Peroxisome Proliferator-Activated Receptor γ Agonist Treatment Reduces Amyloid-β Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice. J. Biol. Chem. 290:21591-21602, 2015 PMID: 26163517
O'Brien DE, Alter BJ, Satomoto M, Morgan CD, Davidson S, Vogt SK, Norman ME, Gereau GB, Demaro JA 3rd, Landreth GE, Golden JP, Gereau RW 4th. ERK2 Alone Drives Inflammatory Pain But Cooperates with ERK1 in Sensory Neuron Survival. J Neurosci. 35:9491-9507, 2015. PMID: 26109671
Richardson ET, Shukla S, Nagy N, Boom WH, Beck RC, Zhou L, Landreth GE and Harding CV. ERK Signaling is Essential for Macrophage Development. PLoS One. 2015 Oct 7;10(10):e0140064. doi: 10.1371/journal.pone.0140064. eCollection 2015. PMID: 26445168
Ghosal, K., Haag, M., Verghese, P. West, T., Veenstra, T., Bateman, R., Holtzman, DM and Landreth, G. A Randomized Controlled Study to Evaluate the Effect of Bexarotene on Amyloid-β and Apolipoprotein E Metabolism in Healthy Subjects. Alz Dem: Trans Res. Clin Inv. 2:110-120
Ostrowski SM, Johnson K, Siefert M, Shank S, Sironi L, Wolozin B, Landreth GE, Ziady AG. Simvastatin inhibits protein isoprenylation in the brain.
Neuroscience. 2016 Aug 4;329:264-74.
Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, Ransohoff RM, Lamb BT, Landreth GE. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer's disease.J Neurosci. 2017 Jan 18;37(3):637-647. PMID:28100745
Garcia-Mesa Y, Jay TR, Checkley MA, Luttge B, Dobrowolski C, Valadkhan S, Landreth GE, Karn J, Alvarez-Carbonell D. Immortalization of primary microglia: a new platform to study HIV regulation in the central nervous system. J Neurovirol. 2016 Nov 21. [Epub ahead of print] PMID:27873219
Huuskonen MT, Loppi S, Dhungana H, Keksa-Goldsteine V, Lemarchant S, Korhonen P, Wojciechowski S, Pollari E, Valonen P, Koponen J, Takashima A, Landreth G, Goldsteins G, Malm T, Koistinaho J, Kanninen KM. Bexarotene targets autophagy and is protective against thromboembolic stroke in aged mice with tauopathy. Sci Rep. 2016 Sep 14;6:33176. doi: 10.1038/srep33176 PMID:27624652
Courtney, R and Landreth, G. Liver X Receptors and their roles in brain metabolism and inflammation - from development to disease. Trends Endocrinol Metab. 27:404-14,, 2016 PMID: 27113081?