Williamson and colleagues make an interesting and provocative link between immunity and memory. The central theme of their paper is that neonatal bacterial insult at the level of the periphery can have long-lasting negative effects on learning and memory later in adult life. Their work recalls that of Nobel laureate Mario Capecchi, who was the first to show a brain-immune connection with psychiatric disease. Specifically, his group demonstrated that deletion of the homeobox gene Hoxb8 in microglia profoundly disrupted neuronal physiology, resulting in disturbance of mouse circadian rhythms and development of the hair-pulling disease, trichotillomania (Greer and Capecchi, 2002; Chen et al., 2010). Capecchi and coworkers were able to ascribe their effects solely to microglia by performing a series of elegant rescue and microglia disease-transfer experiments that were groundbreaking (Chen et al., 2010).

Capecchi originally proposed both cell-surface and soluble factor mechanisms for microglia-neuron interaction. In the present paper, the authors have focused on the...  Read more

Williamson and colleagues make an interesting and provocative link between immunity and memory. The central theme of their paper is that neonatal bacterial insult at the level of the periphery can have long-lasting negative effects on learning and memory later in adult life. Their work recalls that of Nobel laureate Mario Capecchi, who was the first to show a brain-immune connection with psychiatric disease. Specifically, his group demonstrated that deletion of the homeobox gene Hoxb8 in microglia profoundly disrupted neuronal physiology, resulting in disturbance of mouse circadian rhythms and development of the hair-pulling disease, trichotillomania (Greer and Capecchi, 2002; Chen et al., 2010). Capecchi and coworkers were able to ascribe their effects solely to microglia by performing a series of elegant rescue and microglia disease-transfer experiments that were groundbreaking (Chen et al., 2010).

Capecchi originally proposed both cell-surface and soluble factor mechanisms for microglia-neuron interaction. In the present paper, the authors have focused on the pro-inflammatory cytokine interleukin-1 β (IL-1β) as a central mediator of defective hippocampus-dependent memory. Specifically, the authors postulate a "two hit" model, where neonatal rats first encounter peripheral E. coli challenge and then have a second hit with the bacterial endotoxin, LPS. In this scenario, adult rats exhibit greatly elevated IL-1β levels restricted to the hippocampus, and perform poorly in a fear-conditioning behavioral assay. These effects paralleled microglial, but not astroglial activation, and occurred with neuronal inhibition as determined by expression of key microglial-neuron cell-surface interaction molecules (CD200-CD200R and CX3CL1-CX3CR1). Furthermore, the authors were able to demonstrate durable enhancement of IL-1β expression both in vivo and ex vivo in cultured microglia, and the anti-inflammatory agent minocycline was able to prevent exaggerated hippocampal IL-1β response and memory impairment in adult rats infected when they were neonates.

Like any thought-provoking work, the Williamson paper raises a number of questions. For example, it would be interesting to know whether IL-1β is upregulated in the hippocampus during the normal course of learning and memory, in the absence of bacterial challenge. Also, it has previously been shown that neuronal CD22 interacts with microglial CD45 to dampen down microglial activation (Mott et al., 2004). Perhaps the authors might also observe dysregulation of the CD22-CD45 axis in their two-hit model. Finally, while the authors’ conclusion that microglial IL-1β is the source of their behavioral phenotype may be valid, their data are mostly descriptive to this effect. It would be interesting to perform their two-hit model experiments in mice either sufficient for or deficient in IL-1β or caspase-1 (upstream of IL-1β) to definitively show this.

References:
Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, Capecchi MR. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell. 2010 May 28;141(5):775-85. Abstract

Greer JM, Capecchi MR. Hoxb8 is required for normal grooming behavior in mice. Neuron. 2002 Jan 3;33(1):23-34. Abstract

Mott RT, Ait-Ghezala G, Town T, Mori T, Vendrame M, Zeng J, Ehrhart J, Mullan M, Tan J. Neuronal expression of CD22: novel mechanism for inhibiting microglial proinflammatory cytokine production. Glia. 2004 May;46(4):369-79. Abstract

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Comment by Debomoy Lahiri and Bryan Maloney
The previously proposed LEARn (Latent Early-life Associated Regulation) pathway may explain the recently featured results from Chumley and Kahn and from Knuessel et al. regarding infection and AD. Work such as theirs that draws pathways between environmentally induced stress, such as infection, and AD (or AD-like results in model animals) significantly adds to our understanding of the etiology and prevention of AD. However, we would like to point out that the concept of AD as a “two-hit” (actually “n-hit”) disorder is not quite novel. We have previously proposed that a significant proportion of sporadic AD likely arises through latent influences of environment (Lahiri et al., 2009a). We have previously reported latent induction of expression of AD-related genes from early life environmental stress in mice (Basha et al., 2005 and ARF related news story) and in monkeys, and presented this as the “latent early-life associated regulation” (LEARn) model of...  Read more

Comment by Debomoy Lahiri and Bryan Maloney
The previously proposed LEARn (Latent Early-life Associated Regulation) pathway may explain the recently featured results from Chumley and Kahn and from Knuessel et al. regarding infection and AD. Work such as theirs that draws pathways between environmentally induced stress, such as infection, and AD (or AD-like results in model animals) significantly adds to our understanding of the etiology and prevention of AD. However, we would like to point out that the concept of AD as a “two-hit” (actually “n-hit”) disorder is not quite novel. We have previously proposed that a significant proportion of sporadic AD likely arises through latent influences of environment (Lahiri et al., 2009a). We have previously reported latent induction of expression of AD-related genes from early life environmental stress in mice (Basha et al., 2005 and ARF related news story) and in monkeys, and presented this as the “latent early-life associated regulation” (LEARn) model of sporadic/idiopathic neuropsychiatric disease etiology (Lahiri and Maloney, 2010). Briefly, our LEARn model proposes that AD is the result of multiple “hits” against a patient. Such “hits” may include a genetic risk factor (such as ApoE4), but would also include exposure to environmental toxins, heavy metals, variations in life events such as disease exposure, levels of dietary cholesterol, or even interpersonal and sociocultural factors such as emotional stress during childhood, educational attainment, or economic status.

One of the hits is likely to be early in life (Basha et al., 2005). If such a “first hit” is lacking, further hits would usually be insufficient to cause AD. However, even a first hit would be insufficient, in and of itself, to result in AD. It would be the combined hits that lead to AD. LEARn further proposes a testable mechanism. The effects of the first hit and later hits would be latently preserved as epigenetic modifications to DNA and chromatin. Eventually, if hits have accumulated in critical regions of disease-associated genes, AD will result (Lahiri et al., 2009a; Lahiri and Maloney, 2010). Infection has already been shown to result in functional epigenetic modifications, such as changes in DNA methylation and oxidation (Katoh, 2007; Paschos and Allday, 2010; Cabrera et al., 2011; Chakraborty et al., 2011). Immune stimulation/inflammation from multiple causes is a known mechanism for alterations in DNA methylation and oxidation (Risom et al., 2005; Jawad et al., 2011; Saito et al., 2011; Weill et al., 2011). It is, therefore, reasonable to suggest that the results of Chumley and Kahn and of Kneussel et al. may likely reflect such an effect tied to AD-like conditions in model animals.

However, multiple potential causes exist for epigenetic modification. This suggests that infection may act as one likely but not necessary only possible “hit” in AD etiology, if AD is determined to be a disease related to epigenetic regulation. It should be noted that we have already explicitly drawn parallels between a possible “n-hit” model of AD (LEARn) and currently accepted oncological models (Lahiri et al., 2009a). In some ways, the results of Kneussel’s and Chumley’s groups are reminiscent of early results in the “war on cancer” that promised to attribute all or most cancer to infections. While this hypothesis did not directly pan out, it did lead to a broader oncological model based on induced changes in the epigenome, of which infection is one potential cause. Significant differences in DNA methylation have been found in several disorders, including schizophrenia, bipolar disorder, suicide following abuse during childhood, and AD, among others (Heindel et al., 2006; Jirtle and Skinner, 2007; Dosunmu et al., 2009). More specifically, comparison of DNA methylation for selected gene sequences between AD and non-AD brain samples determined disease-associated differences in DNA methylation levels (Wang et al., 2008; Mastroeni et al., 2010). Likewise, a pair of monozygotic twins had been raised together but was discordant for AD. They had differential DNA methylation in temporal neocortical neurons (Mastroeni et al., 2009a; Mastroeni et al., 2009b).

It may be tempting to dismiss these as prenatal “imprintation” effects, but it has been established that genomic DNA methylation can and does change across a large proportion of the human population (Bjornsson et al., 2008). The results reported by Alzforum certainly agree with the LEARn model, which has also proposed specific hypotheses to test environmental influences, consisting of 1) target sites within gene regulatory regions sensitive to epigenetic modification (e.g., unusually high or low concentrations of “CpG” and “GG” dimers); 2) potential critical time points in lifespan for environmental exposures (e.g., early development, midlife, etc.); and 3) environmental factors that tend to alter epigenetic markers. These elements would be combined with knowledge of candidate genes gained by linkage association studies to produce more specific, broadly applicable pathways for AD etiology.

This is, of course, not to denigrate the work recently reported in Alzforum. Confirmation of a potentially important model for AD etiology is always welcome. However, AD as a “multiple-hit” disorder with significant environmental input is an idea that has been explicitly proposed before and overlooked by the Alzforum.

References:
Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, Lahiri DK, Zawia NH. The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J Neurosci. 2005 Jan 26;25(4):823-9. Abstract

Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekström TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason V, Feinberg AP. Intra-individual change over time in DNA methylation with familial clustering. JAMA. 2008 Jun 25;299(24):2877-83. Abstract

Cabrera G, Barría C, Fernández C, Sepúlveda S, Valenzuela L, Kemmerling U, Galanti N. DNA repair BER pathway inhibition increases cell death caused by oxidative DNA damage in Trypanosoma cruzi. J Cell Biochem. 2011 Aug;112(8):2189-99. Abstract

Chakraborty SP, Kar Mahapatra S, Sahu SK, Das S, Tripathy S, Dash S, Pramanik P, Roy S. Internalization of Staphylococcus aureus in lymphocytes induces oxidative stress and DNA fragmentation: possible ameliorative role of nanoconjugated vancomycin. Oxid Med Cell Longev. 2011;2011:942123. Abstract

Dosunmu R, Wu J, Adwan L, Maloney B, Basha MR, McPherson CA, Harry GJ, Rice DC, Zawia NH, Lahiri DK. Lifespan profiles of Alzheimer's disease-associated genes and products in monkeys and mice. J Alzheimers Dis. 2009;18(1):211-30. Abstract

Heindel JJ, McAllister KA, Worth L, Tyson FL. Environmental epigenomics, imprinting and disease susceptibility. Epigenetics. 2006 Jan-Mar;1(1):1-6. Abstract

Jawad N, Direkze N, Leedham SJ. Inflammatory bowel disease and colon cancer. Recent Results Cancer Res. 2011;185:99-115. Abstract

Jirtle RL, Skinner MK. Environmental epigenomics and disease susceptibility. Nat Rev Genet. 2007 Apr;8(4):253-62. Abstract

Katoh M. Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. Cancer Biol Ther. 2007 Jun;6(6):832-9. Abstract

Lahiri DK, Maloney B. The "LEARn" (Latent Early-life Associated Regulation) model integrates environmental risk factors and the developmental basis of Alzheimer's disease, and proposes remedial steps. Exp Gerontol. 2010 Apr;45(4):291-6. Abstract

Lahiri, D.K., Maloney, B. and Zawia, N.H., 2009a. The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. Mol. Psychiatry 14, 992-1003. Abstract

Mastroeni, D., Coleman, P.D., Grover, A., Sue, L., McKee, A. and Rogers, J., 2009a. Differential DNA methylation in neurons of identical twins discordant for Alzheimer’s disease. Alzheimers Dement. 5, P145.

Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J. Epigenetic changes in Alzheimer's disease: decrements in DNA methylation. Neurobiol Aging. 2010 Dec;31(12):2025-37. Abstract

Mastroeni D, McKee A, Grover A, Rogers J, Coleman PD. Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer's disease. PLoS One. 2009;4(8):e6617. Abstract

Paschos K, Allday MJ. Epigenetic reprogramming of host genes in viral and microbial pathogenesis. Trends Microbiol. 2010 Oct;18(10):439-47. Abstract

Risom L, Møller P, Loft S. Oxidative stress-induced DNA damage by particulate air pollution. Mutat Res. 2005 Dec 30;592(1-2):119-37. Abstract

Saito S, Kato J, Hiraoka S, Horii J, Suzuki H, Higashi R, Kaji E, Kondo Y, Yamamoto K. DNA methylation of colon mucosa in ulcerative colitis patients: correlation with inflammatory status. Inflamm Bowel Dis. 2011 Sep;17(9):1955-65. Abstract

Wang SC, Oelze B, Schumacher A. Age-specific epigenetic drift in late-onset Alzheimer's disease. PLoS One. 2008;3(7):e2698. Abstract

Weill FS, Cela EM, Ferrari A, Paz ML, Leoni J, Gonzalez Maglio DH. Skin exposure to chronic but not acute UV radiation affects peripheral T-cell function. J Toxicol Environ Health A. 2011 Jan;74(13):838-47. Abstract

View all comments by Debomoy Lahiri