Landreth Lab

The research lab of Dr. Gary Landreth focuses on the biological basis of Alzheimer’s disease (AD)—specifically how genetic risks factor influence disease pathogenesis. The work in the laboratory employs contemporary animal models of AD. This team of scientists are particularly interested in how neuroinflammation participates in AD initiation and progression and are investigating how variants of an immune gene, Trem2, greatly elevates risk for AD.

Active Research

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. The Landreth Lab was amongst the first team of medical scientists to identify the receptors for fibrillar forms of Alzheimer’s disease. The team 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. The lab has validated its involvement by genetic inactivation of the fA receptors and signaling elements. Significantly, these scientists 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. Scientists in the Landreth Lab were the first to document the efficacy of agonists of these receptors in CNS disorders, most prominently Alzheimer’s disease. The lab team 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, these medical scientists translated this work into clinical trials of PPAR 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. The lab is currently 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. Investigators in the Landreth Lab 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 PPARor RXR agonists resulted in enhanced clearance of soluble forms of A 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.

National Institutes of Health, Landreth (PI), 1 R01 AG043522-01, 8/1/2013-7/31/2018
Functional significance of amyloid dynamics and deposition in the AD brain.

National Institutes of Health, Lamb and Landreth (PIs), 1RF1AG051495-01, 09/30/2015 – 08/31/2020
Central and Peripheral Roles of TREM2 in Alzheimer’s Disease

National Institutes of Health, Landreth (PI), 1 R01 AG050597-01A1, 4/1/2016-3/31/2021
Actions of Nuclear Receptors on TREM2+ myeloid cells and microglia in AD brain

Alzheimer’s Association IIRG, 9/30/2015-9/30/2018
Roles of TREM2 in AD Pathogenesis

Weston Brain Institute, 3/1/2017-3/1/2018
Postdoctoral Fellow Award

Roxanne Williams, Lab manager
Victoria von Saucken, Research Assistant II
Miguel Moutinho, Postdoctoral Fellow
Juan Francisco Codocedo, Postdoctoral Fellow
Brad Casali, Graduate Student
Paul Cheng-Hathaway, Graduate Student

Recent Publications

Therapeutic potential of nuclear receptor agonists in Alzheimer’s disease. Moutinho M, Landreth GE. J Lipid Res. 2017 Mar 6.. [Epub ahead of print]

Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease.
Mariani MM, Malm T, Lamb R, Jay TR, Neilson L, Casali B, Medarametla L, Landreth GE. Sci Rep. 2017 Feb 16;7:42270

Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer’s Disease. Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, Ransohoff RM, Lamb BT, Landreth GE. J Neurosci. 2017 Jan 18;37(3):637-647.

LXR Regulation of Brain Cholesterol: From Development to Disease.
Courtney R, Landreth GE. Trends Endocrinol Metab. 2016 Jun;27(6):404-14.

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. Skerrett R, Pellegrino MP, Casali BT, Taraboanta L, Landreth GE. J Biol Chem. 2015 Aug 28;290(35):21591-602.

Omega-3 Fatty Acids Augment the Actions of Nuclear Receptor Agonists in a Mouse Model of Alzheimer’s Disease. Casali BT, Corona AW, Mariani MM, Karlo JC, Ghosal K, Landreth GE. J Neurosci. 2015 Jun 17;35(24):9173-81

Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. Savage JC, Jay T, Goduni E, Quigley C, Mariani MM, Malm T, Ransohoff RM, Lamb BT, Landreth GE. J Neurosci. 2015 Apr 22;35(16):6532-43.

The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway. Pucilowska J, Vithayathil J, Tavares EJ, Kelly C, Karlo JC, Landreth GE. J Neurosci. 2015 Feb 18;35(7):3190-200.

TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. 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. J Exp Med. 2015 Mar 9;212(3):287-95

Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. Mandrekar-Colucci S, Karlo JC, Landreth GE. J Neurosci. 2012 Jul 25;32(30):10117-28.

ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE. Science. 2012 Mar 23;335(6075):1503-6