Inflammation serves a purpose, but when it goes unchecked it can cause irreparable damage. On September 30 in Proceedings of the National Academy of Sciences, scientists led by Frank LaFerla and Rodrigo Medeiros at the University of California, Irvine, reported that TOM1 plummets in the brains of Alzheimer’s disease patients and in mouse models of amyloidosis. TOM1 is a protein that yanks inflammatory receptors, including IL-1R1, from the cell surface. Restoring it in the mice assuaged inflammation, Aβ plaque burden, and cognitive decline, while knocking down TOM1 expression aggravated these problems. The researchers proposed that boosting the TOM1 signaling pathway in AD could become a therapeutic strategy to promote the beneficial effects of inflammation while minimizing the detrimental ones.
- TOM1 levels are reduced in AD brains, and in Aβ models.
- The protein internalizes interleukin 1 receptors, limits inflammatory responses in AD mouse models.
- Boosting TOM1 levels spurs microglia to clear Aβ.
Neuroinflammation has emerged as a major player in AD. Among the many inflammatory pathways implicated in the disease, signaling through IL-1β reportedly worsens AD pathogenesis (Kitazawa et al., 2011; Sciacca et al., 2003). Levels of this cytokine rise in the brain, cerebrospinal fluid, and plasma in people with AD (Licastro et al., 2000). In the 3xTg mouse model, IL-1β rises as Aβ accumulates in neurons (Oct 2005 news). Neurons express the cytokine’s main receptor, IL-1R1. Notably, when IL-1β latches on to this receptor, the pair are internalized to endosomes by Target of Myb, aka TOM1. This is a cytosolic protein required for endocytic trafficking and resolution of the inflammatory response (Brissoni et al., 2006; Katoh et al., 2004).
First author Alessandra Martini and colleagues investigated whether disrupted TOM1 signaling could be a factor in inflammatory responses in AD. First, they found that levels of the protein in brain extracts of three to eight people with AD were about half those in a similar number of age-matched controls, while IL-1R1 was about threefold higher. Likewise, TOM1 dropped, while IL-1R1 rose, in cultured primary mouse neurons in response to treatment with a preparation of soluble Aβ. Compared with wild-type mice, 3xTg mice had less TOM1, and more IL-1R1 and IL-1β, in the hippocampus.
To ask if TOM1 expression might affect the inflammatory milieu in the AD brain, Martini and colleagues injected the hippocampi of 9-month-old 3xTg mice with adeno-associated virus constructs that either led to overexpression of TOM1, or knocked it down. The latter activated genes involved in inflammatory pathways, including cytokines, chemokines, and complement components, and boosted IL-1R1 expression on neuronal cell membranes. Overexpressing TOM1 reduced neuronal IL-1R1.
As for microglia, knocking down TOM1 in 3xTg mice caused them to round up and retract their processes, while overexpressing TOM1 triggered an uptick in Aβ inside microglial phagolysosomes, according to immunohistochemical staining of microglia in the 3xTg mouse brain (see image below). TOM1 overexpression also reduced Aβ burden, while TOM1 knockdown ramped it up.
In cultured iPSC-derived microglia, boosting TOM1 dramatically enhanced phagocytosis of Aβ fibrils. The microglial studies suggested to the authors that in addition to internalizing inflammatory receptors on neurons, TOM1 also directly supports microglial phagocytosis and Aβ clearance.
Might TOM1 affect learning and memory? Indeed, when 3xTG mice overexpressed the protein, they located a hidden platform as quickly as wild-type mice, while lack of TOM1 exacerbated spatial memory problems.
Together, the findings indicate that TOM1 facilitates IL-1R signaling in neurons, and ramps up Aβ phagocytosis in microglia. While the relative contributions of these TOM1 functions to overall Aβ pathogenesis and cognitive decline remain to be ironed out, the researchers believe that bolstering TOM1 signaling in the AD brain could restore a homeostatic immune response. The authors emphasized to Alzforum that the findings highlight the importance of inflammatory signaling in neurons, as opposed to solely in glia.
LaFerla said the team are now trying to understand what causes TOM1 expression to drop in AD in the first place.—Jessica Shugart
Research Models Citations
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- Sciacca FL, Ferri C, Licastro F, Veglia F, Biunno I, Gavazzi A, Calabrese E, Martinelli Boneschi F, Sorbi S, Mariani C, Franceschi M, Grimaldi LM. Interleukin-1B polymorphism is associated with age at onset of Alzheimer's disease. Neurobiol Aging. 2003 Nov;24(7):927-31. PubMed.
- Licastro F, Pedrini S, Caputo L, Annoni G, Davis LJ, Ferri C, Casadei V, Grimaldi LM. Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer's disease: peripheral inflammation or signals from the brain?. J Neuroimmunol. 2000 Feb 1;103(1):97-102. PubMed.
- Brissoni B, Agostini L, Kropf M, Martinon F, Swoboda V, Lippens S, Everett H, Aebi N, Janssens S, Meylan E, Felberbaum-Corti M, Hirling H, Gruenberg J, Tschopp J, Burns K. Intracellular trafficking of interleukin-1 receptor I requires Tollip. Curr Biol. 2006 Nov 21;16(22):2265-70. PubMed.
- Katoh Y, Shiba Y, Mitsuhashi H, Yanagida Y, Takatsu H, Nakayama K. Tollip and Tom1 form a complex and recruit ubiquitin-conjugated proteins onto early endosomes. J Biol Chem. 2004 Jun 4;279(23):24435-43. Epub 2004 Mar 26 PubMed.
- Li Y, Liu L, Barger SW, Griffin WS. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J Neurosci. 2003 Mar 1;23(5):1605-11. PubMed.
- Hein AM, Stasko MR, Matousek SB, Scott-McKean JJ, Maier SF, Olschowka JA, Costa AC, O'Banion MK. Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice. Brain Behav Immun. 2010 Feb;24(2):243-53. PubMed.
- Martini AC, Gomez-Arboledas A, Forner S, Rodriguez-Ortiz CJ, McQuade A, Danhash E, Phan J, Javonillo D, Ha JV, Tram M, Trujillo-Estrada L, da Cunha C, Ager RR, Davila JC, Kitazawa M, Blurton-Jones M, Gutierrez A, Baglietto-Vargas D, Medeiros R, LaFerla FM. Amyloid-beta impairs TOM1-mediated IL-1R1 signaling. Proc Natl Acad Sci U S A. 2019 Oct 15;116(42):21198-21206. Epub 2019 Sep 30 PubMed.