Epigenetic Shenanigans—In AD, Chromatin Opens Up in Blood Immune Cells

Immune cells in the blood may be intimately involved with Alzheimer’s pathogenesis in the brain. At least, according to their chromatin. A study published January 31 in Neuron reported that in people with AD, the circulating cells—especially CD8+ T cells and monocytes—relax stretches of their chromosomes, giving transcription factors easy access to inflammatory promoters and enhancers. Led by David Gate at Northwestern University in Chicago, the study tied ApoE genotype to epigenetic changes in the peripheral cells, suggesting they help explain genetic risk. In support of this, AD risk genes were among those most ramped-up. 

  • In AD, sections of chromatin unfold in peripheral immune cells.
  • This allows for increased expression of inflammatory genes.
  • ApoE4 genotype exacerbates some of these effects.

“This exciting study highlights the growing body of work supporting peripheral immune cell involvement in AD neuropathology,” wrote Mehdi Jorfi and Rudolph Tanzi of Massachusetts General Hospital in Boston in a joint comment to Alzforum. “It underscores a growing paradigm … in which the disease extends beyond solely brain-related pathology, and involves the … intricate interplay between peripheral immune cells and the brain.”

The findings dovetail with recent studies implicating systemic immune cells, particularly CD8+ T cells, in neurodegeneration. As a postdoc in Tony Wyss-Coray’s lab at Stanford University, Gate previously spotted CD8+ T cells congregating in the cerebrospinal fluid and within the brains of people with AD and PD (Jan 2020 news). Later, at Northwestern, Gate found these T cells mingling with microglia around plaques, where the two cell types expressed cognate chemokine/receptor pairs (Dec 2022 news). Similarly, in a three-dimensional cell culture model of AD, Tanzi’s group found that chemokine-recruited CD8+ T cells teamed up with microglia to destroy vulnerable neurons (Sep 2023 news).

Because epigenetic changes, such as chromatin accessibility, signify previous and ongoing responses in immune cells, first author Abhirami Ramakrishnan and colleagues decided to map them out. They used single-cell ATAC-Seq and RNA-Seq to compare both chromatin accessibility and gene expression in peripheral blood cells from 26 cognitively normal people, and 29 with AD. First, they looked for chromatin that was structurally different between the two groups. So-called differentially accessible regions (DARs) were found in most immune cell types, with CD8+ T cells having more than other cells. The majority of these regions were more accessible in people with AD than in controls, and many of the open stretches overlapped with genes involved in immune cell activation and cytokine signaling. Next, the researchers identified differentially expressed genes (DEGs) using their scRNA-Seq data. Lo and behold, a substantial proportion of these DEGs overlapped with the DARs. These overlaps—indicative of epigenetic regulation of gene expression—were most abundant in CD8+ T effector cells and monocytes. As a NeuroResource study, all this epigenetic and transcriptomic data are freely available for sifting by other researchers (see https://gatelabnu.shinyapps.io/ad_apoe_rna/).

In people with AD, what were some of the highlights of Ramakrishnan’s analysis? In monocytes, open stretches of chromatin overlapped with the gene for subunit 2 of NF-kB, and this correlated with elevated expression of the transcription factor. To Gate, this suggests these cells are in a primed, activated state. Likewise, monocytes opened chromatin near ABCA1, an AD risk gene that encodes an apolipoprotein that transfers lipids to ApoE.

CD8+ T effector memory cells bust open the CXCR3 gene promotor, and ramp up expression of this chemokine receptor at both the transcript and protein levels. Ramakrishnan spotted CXCR3+ CD8+ T cells in postmortem hippocampus and leptomeninges samples from people with AD, suggesting that this receptor might help the T cells enter the brain (image below). Indeed, Jorfi and colleagues had reported that astrocytes expressing the CXCR3 ligand, CXCL10, guide T cells to human AD neuron-glia cocultures (Jorfi et al., 2023).

Beckoned to the Brain? T cells (CD3+, pink) expressing CD8 (red) and the chemokine receptor CXCR3 (green) loiter in the hippocampus of a person with AD (see arrows). [Courtesy of Ramakrishnan et al., Neuron, 2024.]

ApoE is the strongest AD risk gene, and the apolipoprotein it encodes has long been known to play a role in immunity and inflammation, both in and outside of the brain (for example, Gale et al., 2014; Oct 2021 news). Might ApoE genotype influence chromatin accessibility in these peripheral immune cells? To address this, the researchers stratified chromatin accessibility by APOE genotype. In a nutshell, they found a stepwise rise in the number of DARs with each copy of ApoE4. Among ApoE4 carriers, in AD, APOE3/4 and APOE4/4 monocytes had more open chromatin than APOE3/3 cells, and a corresponding uptick in transcripts encoding several inflammatory chemokines, including CCL4L2, CCL3L1, and CXCL2.

Because many AD risk genes are expressed by microglia, these brain resident immune cells have received much of the blame for driving AD risk. However, Gate pointed out that about half of risk genes are also expressed by peripheral immune cells, suggesting these cells might contribute as well. In support of this idea, the researchers identified open stretches of chromatin around several AD risk genes in immune cells from people with AD. The INPP5D gene was exposed and overexpressed in B cells and NK cells, as were clusterin and BIN1 genes in CD8+ T cells. In ApoE4 carriers, some of these associations were even stronger. “These findings suggest that AD risk factors are not contributing solely to altered microglial responses in the AD brain, but may also contribute to dysregulated peripheral immune function in AD,” the authors wrote.

To what extent AD risk genes drive disease pathogenesis via peripheral immune cells—as opposed to brain resident microglia—remains to be seen, Gate said. However, there is a possibility that the peripheral cells might lie further upstream in the AD cascade than previously thought. Gate noted that viral infections and exposure to pollutants—both of which have been linked to AD risk—can leave an epigenetic mark on peripheral immune cells. “It’s possible that these exposures contribute to AD by promoting damaging responses in these circulating cells,” he said. On the flip side, the epigenetic changes may reflect a response to the AD pathology already in the brain. Tracking these exposures and their epigenetic consequences over time will be necessary to understand how they relate to AD, he said.

To Wyss-Coray’s mind, the links between ApoE4 genotype, expression of AD risk genes, and activation of peripheral immune cells were the most intriguing in the study. “Although still controversial, a growing number of studies suggest that monocytes or related circulatory cells can enter the aging or AD brain and assume roles typically assigned to microglia,” he wrote. “If such infiltrating cells produce chemokines, they may attract other immune cells to the brain producing a possibly damaging immune environment” (comment below).

Jason Ulrich of Washington University in St. Louis wondered if APOE4 influences on peripheral immunity/inflammation could play a role in the development of cerebral amyloid angiopathy, which is linked with APOE4 in mouse models and humans. Both ApoE4 genotype and CAA have been tied to hemorrhagic side effects of amyloid-targeted immunotherapies (Aug 2023 conference news; Jan 2024 news). 

Tsuneya Ikezu of the Mayo Clinic in Jacksonville, Florida, wrote that while the combination of epigenetic and transcriptomic methods in the study was a significant advance, he believes the sample size was not large enough to make comparisons by ApoE genotype. Gate acknowledged that the numbers were small, but that the cost of these extensive analyses precluded larger sample sizes, for now.—Jessica Shugart

Comments

  1. In recent decades, substantial strides have been made in unraveling the genetic factors and biological mechanisms underlying Alzheimer’s disease, with a primary focus on microglia as the brain's resident immune cells. However, it is now widely recognized that both innate and adaptive immune responses are active players in neurodegenerative diseases, with adaptive immunity, notably involving T cells, emerging as a significant contributor to AD neuropathology (Jorfi et al., 2023; Chen and Holtzman, 2023). Notable observations include increased T-cell presence in various brain regions of AD patients and AD-like mouse models (Gate et al., 2020; Laurent et al., 2017; Merlini et al., 2018). Previously, we showed a significantly higher percentage of human CD8+ T cells infiltrating into AD neural–glial cultures. We also demonstrated a significantly increased percentage and absolute number of extravascular CD4+ and CD8+ T cells in the brains of 5×FAD mice (Jorfi et al., 2023). Another recent study from the Holtzman lab showed a significant enrichment of CD8+ T cells in the parenchyma of mice expressing tau and APOE4, indicating T-cell involvement in tauopathy and neurodegeneration (Chen et al., 2023). 

    This exciting work from the Gate lab highlights the growing body of work supporting peripheral immune cell involvement in AD neuropathology and underscores a growing paradigm in AD in which the disease extends beyond solely brain-related pathology and involves the immune system and the intricate interplay between peripheral immune cells and the brain. Notably, the authors reveal a surprising increase in open chromatin regions in peripheral immune cells of AD patients. They also identified an AD-specific RELA binding site in the NFkB2 gene. Their data also suggest an enhanced peripheral immune inflammatory response in AD APOE ε4/ε4 carriers that may influence AD risk or disease severity in these subjects. Importantly, they also detected a cis regulatory element associated with CXCR3 expression in CD8+ T cells. Additionally, the authors detected CXCR3+ CD8+ T cells in the AD hippocampus and meninges.

    Previously, we demonstrated key roles for CXCL10 and its receptor CXCR3 in orchestrating T-cell infiltration and neuronal damage. We showed that infiltrating CD8+ T cells express the CXCR3 receptor in 5×FAD mouse brains. We also found that blocking the CXCL10-CXCR3 axis using a neutralizing antibody against CXCR3 inhibited the infiltration of CD8+ T cells into AD neural–glial cultures and significantly attenuated neurodegeneration (Jorfi et al., 2023). Our study suggests the potential for therapeutic interventions for AD based on targeting the chemokine-chemokine receptor axis to reduce CD8+ T cell infiltration into the brains of patients with AD. Similarly, it has also been shown that immune depletion of T cells significantly ameliorates brain atrophy, neuronal loss, and behavioral impairment (Chen et al., 2023). Specifically, previous studies showed that disease pathology in a mouse model that combines tauopathy with human ApoE4 expression is associated with detrimental microglia and CD8+ cells; depletion of each of these cell populations diminishes disease manifestations (Chen et al., 2023). Furthermore, targeted interventions against specific immune pathways involving T cells hold promise as potential therapeutic strategies for AD. Future studies should focus on elucidating the specific T cell receptors that undergo expansion and identifying the antigens that microglia present in AD. Moreover, it would also be highly important to examine specific T cell subpopulations, including, but not limited to, effector CD4+ T cells, regulatory T cells, cytotoxic CD8+ T cells, and exhausted CD8+ T cells, as well as investigating the essential immune modulators or checkpoint blockade molecules involved in AD progression.

    The investigation of infiltrating T cells and their functions in the AD brain represents a key research area. Recent studies suggest that microglia may play a role in recruiting CD8+ T-cells into the CNS, thereby contributing to neurodegeneration, including tau pathology models. The authors in this paper found that T cells interact with plaque-associated microglia in the AD brain. We previously found that CD8+ T cells enhance microglial activation and exacerbate neuroinflammation and neurodegeneration in AD cultures. Our findings also emphasize the role of infiltrating T cells in triggering INF-/inflammatory-associated pathways. We observed a robust increase in proinflammatory cytokines (e.g., IL-2, IL-15, TNF-α and IFN-γ) after infiltration of CD8+ T cells into AD cultures with microglia (Jorfi et al., 2023). 

    This study, together with prior research in AD, poses compelling questions. Could inhibiting interactions between microglia and T cells emerge as a viable therapeutic strategy to mitigate neurodegeneration in AD? It is evident that we are embarking upon a new era in the pursuit of AD treatments, wherein the focus extends beyond pathological proteins to encompass the immune system's capacity to regulate their accumulation in the brain and the neuroinflammatory damage associated with neuroimmune interactions. Future investigations may broaden immunotherapeutic avenues for AD by targeting immune signaling, including the utilization of engineered immune cells. Collectively, this study represents a significant contribution that is poised to catalyze further research into immunotherapies for neurodegenerative diseases.

    References:

    Jorfi M, Maaser-Hecker A, Tanzi RE. The neuroimmune axis of Alzheimer's disease. Genome Med. 2023 Jan 26;15(1):6. PubMed.

    Chen X, Holtzman DM. Emerging roles of innate and adaptive immunity in Alzheimer's disease. Immunity. 2022 Dec 13;55(12):2236-2254. Epub 2022 Nov 8 PubMed.

    Gate D, Saligrama N, Leventhal O, Yang AC, Unger MS, Middeldorp J, Chen K, Lehallier B, Channappa D, De Los Santos MB, McBride A, Pluvinage J, Elahi F, Tam GK, Kim Y, Greicius M, Wagner AD, Aigner L, Galasko DR, Davis MM, Wyss-Coray T. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature. 2020 Jan;577(7790):399-404. Epub 2020 Jan 8 PubMed.

    Laurent C, Dorothée G, Hunot S, Martin E, Monnet Y, Duchamp M, Dong Y, Légeron FP, Leboucher A, Burnouf S, Faivre E, Carvalho K, Caillierez R, Zommer N, Demeyer D, Jouy N, Sazdovitch V, Schraen-Maschke S, Delarasse C, Buée L, Blum D. Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy. Brain. 2017 Jan;140(1):184-200. Epub 2016 Nov 5 PubMed.

    Merlini M, Kirabali T, Kulic L, Nitsch RM, Ferretti MT. Extravascular CD3+ T Cells in Brains of Alzheimer Disease Patients Correlate with Tau but Not with Amyloid Pathology: An Immunohistochemical Study. Neurodegener Dis. 2018;18(1):49-56. Epub 2018 Feb 7 PubMed.

    Jorfi M, Park J, Hall CK, Lin CJ, Chen M, von Maydell D, Kruskop JM, Kang B, Choi Y, Prokopenko D, Irimia D, Kim DY, Tanzi RE. Infiltrating CD8+ T cells exacerbate Alzheimer's disease pathology in a 3D human neuroimmune axis model. Nat Neurosci. 2023 Sep;26(9):1489-1504. Epub 2023 Aug 24 PubMed.

    Chen X, Firulyova M, Manis M, Herz J, Smirnov I, Aladyeva E, Wang C, Bao X, Finn MB, Hu H, Shchukina I, Kim MW, Yuede CM, Kipnis J, Artyomov MN, Ulrich JD, Holtzman DM. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature. 2023 Mar;615(7953):668-677. Epub 2023 Mar 8 PubMed.

    View all comments by Mehdi Jorfi View all comments by Rudy Tanzi

  2. Cognitive decline associated with aging is often the harbinger of an underlying neurodegenerative process ultimately leading to Alzheimer’s disease. Genetic studies have found strong associations between variants in immune genes and AD, but neuroscientists are typically biased to study these genes in resident brain cells. With the advent of large-scale, unbiased transcriptomic and proteomic analysis of brain tissue from the elderly or AD patients, inflammatory pathways are also invariably found to be dysregulated. But can these brain-specific changes be linked or even be attributed to classic immune cell dysfunction in humans? If this were the case, could we monitor the onset and progression of disease in easily accessible blood cells or even target the disease process indirectly?

    The findings from Ramakrishnan in the Gate lab provide intriguing new insight into abnormalities in gene expression in a number of circulating immune cell types, using a combination of genetics and omics tools. While the study is still relatively limited in patient numbers, it provides a first glimpse at epigenetic changes integrated with unbiased gene expression analysis in peripheral immune cells in AD. The authors observe a striking increase in chromatin accessible sites in AD monocytes not previously reported and an intriguing AD-specific RELA binding site in in the NFkB2 gene based on open chromatin sites. It is also very reassuring to see that their unbiased analyses point to, for example, CXCR3 epigenetic changes along with increased transcription in CD8 memory T cells. Notably, Gate et al. previously showed CD8 cells to be clonally expanded in the cerebrospinal fluid of AD patients and suggested related chemokine receptors CXCR4 and CXCR6 to facilitate brain immune cell infiltration.

    Maybe the most intriguing observation of this study is the association between APOE genotype and immune cell transcriptional activation supported by epigenetics, and newly observed epigenetic changes in known AD risk genes dependent on APOE genotype. For example, the authors report a prominent APOE4 dose-dependent increase in activation of immune genes in blood monocytes, particularly genes related to chemokine signaling. Many of these chemokines have been previously reported to be dysregulated in microglia and it will be interesting to understand if circulating monocytes produce chemokines to attract T cells via CXCR family members or if these signaling molecules have independent functions. Although still controversial, a growing number of studies suggest that monocytes, or related circulatory cells, can enter the aging or AD brain and assume roles typically assigned to microglia. If such infiltrating cells produce chemokines, they may attract other immune cells to the brain, producing a possibly damaging immune environment in the brain.

    The study by Ramakrishnan leaves many new questions and an accompanying app allows the community to search for transcriptomic changes to help facilitate hypothesis generation or validation of independent findings. There seem to be particularly strong associations with epigenetic changes in NK cells in APOE4 carriers, an understudied cell type with a broad array of immune functions. 

    View all comments by Tony Wyss-Coray

  3. The dataset described and shared by Ramakrishnan and colleagues is a tremendously rich repository of information on the transcriptional and epigenetic state of the peripheral immune system. Two things initially caught my eye. 

    First, the authors describe increased chromatin accessibility in the CXCR3 gene along with CXCR3 expression in CD8+ TEMRA cells in AD patients. As the authors comment, CD8+ TEMRA cells were previously identified as clonally expanded cells in CSF from AD patients and CXCR3 expression was found to permit T cell entry and toxicity in an AD organoid model from the Tanzi group. Clonally expanded CD8+ TEMRA cells were also elevated in peripheral blood mononuclear cells of ALS-4 patients. In the case of AD, it will be interesting to know how elevations in peripheral CD8+ TEMRA cells correlate with changes in amyloid versus tauopathy.

    Second, the authors describe APOE4-dependent differences in chromatin accessibility in peripheral immune cells. I wonder if APOE4 influences on peripheral immunity/inflammation could play a role in the development of CAA, which is linked with APOE4 in mouse models and in humans.

    View all comments by Jason Ulrich

  4. Apolipoprotein E (APOE) is a multifunctional protein crucial for maintaining lipid homeostasis and metabolism. Certain APOE polymorphisms increase susceptibility to a wide spectrum of diseases in humans, including coronary and peripheral vascular disease, obesity/diabetes, and neurodegenerative diseases, especially Alzheimer's disease (AD) (Igel et al., 2021). The findings of this study investigating the influence of APOE on epigenetic changes in the peripheral immune system in AD are particularly intriguing. Through the utilization of isolated immune cells from human peripheral blood samples, and advanced multi-omic techniques, such as single-cell sequencing (scATAC-Seq, scRNA-Seq, and scTCR-Seq), the study provided a detailed analysis of the immune landscape at the single-cell level. Notably, it revealed APOE4-specific epigenetic and transcriptional changes associated with peripheral immune cells in AD patients, shedding light on potential mechanisms underlying disease pathogenesis.

    Specifically, a stepwise, APOE4 gene dose-dependent increase in chromatin accessibility was identified for nearly all peripheral immune cells, with the upregulation of inflammatory chemokines such as CCL4L2, CCL3L1, and CXCL2, identified in monocytes. While the functional implications of these epigenetic dysregulations require further examination, the discovery of APOE-specific chromatin modifications in peripheral immune cells introduces a new layer of complexity to our understanding of immune dysregulation.

    These findings gain relevance given APOE4’s status as a primary risk factor for AD and for cerebral amyloid angiopathy (CAA), where it is known to exacerbate Aβ aggregation and impair Aβ clearance, thereby accelerating the onset of clinical symptoms in patients. Moreover, APOE4 carriers exhibit the highest incidence of amyloid-related imaging abnormalities (ARIA) in recent clinical trials of amyloid targeting immunotherapies (Loomis et al., 2024). This reflects an increased risk of developing inflammatory changes and cerebrovascular damage that correlates with CAA. 

    The identification of APOE4-specific epigenetic and transcriptional changes in peripheral immune cells is underscored by a recent autopsy report from an individual with two copies of APOE4, linking peripheral immune cell infiltration and perivascular macrophage immune responses to severe cerebral microhemorrhage (Solopova et al., 2023). This echoes our own research, which demonstrates a strong association between perivascular macrophage activation, peripheral monocyte recruitment, and microhemorrhages in an AD model (Taylor et al., 2023). Moreover, the identification of APOE-specific chromatin modifications in peripheral immune cells suggests a potential influence of APOE4 beyond increased CAA accumulation, extending to the activation threshold of myeloid cells, warranting further investigation into its impact on perivascular macrophages, thereby offering additional insights into APOE's role as a risk factor for ARIA.

    Overall, these findings contribute to our understanding of the influence of epigenetics and genetic risk factors on peripheral immune cells in AD. By understanding the interplay between genetics, epigenetic modifications, and immune responses, we can also better comprehend the mechanism of ARIA, ultimately improving treatment outcomes for patients.

    References:

    Igel E, Haller A, Wolfkiel PR, Orr-Asman M, Jaeschke A, Hui DY. Distinct pro-inflammatory properties of myeloid cell-derived apolipoprotein E2 and E4 in atherosclerosis promotion. J Biol Chem. 2021 Sep;297(3):101106. Epub 2021 Aug 21 PubMed.

    Loomis SJ, Miller R, Castrillo-Viguera C, Umans K, Cheng W, O'Gorman J, Hughes R, Budd Haeberlein S, Whelan CD. Genome-Wide Association Studies of ARIA From the Aducanumab Phase 3 ENGAGE and EMERGE Studies. Neurology. 2024 Feb 13;102(3):e207919. Epub 2023 Dec 28 PubMed.

    Solopova E, Romero-Fernandez W, Harmsen H, Ventura-Antunes L, Wang E, Shostak A, Maldonado J, Donahue MJ, Schultz D, Coyne TM, Charidimou A, Schrag M. Fatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer's disease. Nat Commun. 2023 Dec 12;14(1):8220. PubMed.

    Taylor X, Clark IM, Fitzgerald GJ, Oluoch H, Hole JT, DeMattos RB, Wang Y, Pan F. Amyloid-β (Aβ) immunotherapy induced microhemorrhages are associated with activated perivascular macrophages and peripheral monocyte recruitment in Alzheimer's disease mice. Mol Neurodegener. 2023 Aug 30;18(1):59. PubMed.

    View all comments by Xavier Taylor

  5. We read the this paper (Ramakrishnan et al., 2024) with great interest and agree with others’ comments already posted in Alzforum.

    We have long maintained that there is an important role for epigenetic markers in the etiology of AD (Maloney and Lahiri, 2016). In the context of neurodegenerative diseases, we have emphasized epigenetic changes in CNS tissues. The contribution of peripheral immunity and inflammation to AD could be another link between environmental effects and disease etiology. It is often presumed that immune privilege for the brain is nearly absolute; however, this is not the case, and some immune cells can cross from the periphery to the CNS (Galea et al., 2007), and as such could be a possible route to transfer peripheral epigenetic effects to the CNS.

    Ramakrishnan and colleagues further noted APOE genotype-related differences and epigenetic changes in NF-KB2 chromatin also associated with AD. We are reminded of our report of a feedback loop involving NF-κB and Aβ in the stimulation of APOE gene regulation (Du et al., 2005). 

    While the team led by David Gate elegantly reported an APOE genotype effect, we have shown previously that gain or loss of function mutations to some extent can be mirrored by differences in levels of a majority allele (Maloney et al., 2010). Both elements could operate in the development of AD. Admittedly, the associations noted in the paper cannot be presumed to be causal and could as easily result from peripheral conditions induced by AD.

    We hope investigators in the field embrace this new idea. Further mechanistic studies in models that have peripheral immune systems—animal models—would be a good step toward exploring this avenue in addition to tracking potential changes in subjects that may or may not develop AD at some future date. Transgenerational effects (Lahiri et al., 2022) are also worth studying in the future.

    In short, a model that incorporates multiple inputs from biological, social, and environmental data can lead to effective routes of prevention and treatment, and the elegant work by this team at Northwestern University opens up these avenues.

    References:

    Ramakrishnan A, Piehl N, Simonton B, Parikh M, Zhang Z, Teregulova V, van Olst L, Gate D. Epigenetic dysregulation in Alzheimer's disease peripheral immunity. Neuron. 2024 Apr 17;112(8):1235-1248.e5. Epub 2024 Feb 9 PubMed.

    Maloney B, Lahiri DK. Epigenetics of dementia: understanding the disease as a transformation rather than a state. Lancet Neurol. 2016 Jun;15(7):760-74. Epub 2016 May 9 PubMed.

    Galea I, Bechmann I, Perry VH. What is immune privilege (not)?. Trends Immunol. 2007 Jan;28(1):12-8. Epub 2006 Nov 28 PubMed.

    Du Y, Chen X, Wei X, Bales KR, Berg DT, Paul SM, Farlow MR, Maloney B, Ge YW, Lahiri DK. NF-(kappa)B mediates amyloid beta peptide-stimulated activity of the human apolipoprotein E gene promoter in human astroglial cells. Brain Res Mol Brain Res. 2005 May 20;136(1-2):177-88. PubMed.

    Maloney B, Ge YW, Petersen RC, Hardy J, Rogers JT, Pérez-Tur J, Lahiri DK. Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions. Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):185-201. PubMed.

    Lahiri DK, Maloney B, Song W, Sokol DK. Crossing the "Birth Border" for Epigenetic Effects. Biol Psychiatry. 2022 Aug 15;92(4):e21-e23. Epub 2022 Mar 2 PubMed.

    View all comments by Debomoy Lahiri View all comments by Bryan Maloney

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References

News Citations

  1. Attack of the Clones? Memory CD8+ T Cells Stalk the AD, PD Brain
  2. In AD, CSF Immune Cells Hint at Mounting Mayhem in the Brain
  3. In 3D Cell Model of AD, Microglia and CD8+ T Cells Gang Up on Neurons
  4. Even In the Healthy, ApoE4 Stirs Up Trouble, Scientists Say
  5. Is ARIA an Inflammatory Reaction to Vascular Amyloid?
  6. Brain of Woman Who Died on Leqembi Shows Worst-Case Scenario

Mutations Citations

  1. APOE C130R (ApoE4)

Paper Citations

  1. Jorfi M, Park J, Hall CK, Lin CJ, Chen M, von Maydell D, Kruskop JM, Kang B, Choi Y, Prokopenko D, Irimia D, Kim DY, Tanzi RE. Infiltrating CD8+ T cells exacerbate Alzheimer's disease pathology in a 3D human neuroimmune axis model. Nat Neurosci. 2023 Sep;26(9):1489-1504. Epub 2023 Aug 24 PubMed.
  2. Gale SC, Gao L, Mikacenic C, Coyle SM, Rafaels N, Murray Dudenkov T, Madenspacher JH, Draper DW, Ge W, Aloor JJ, Azzam KM, Lai L, Blackshear PJ, Calvano SE, Barnes KC, Lowry SF, Corbett S, Wurfel MM, Fessler MB. APOε4 is associated with enhanced in vivo innate immune responses in human subjects. J Allergy Clin Immunol. 2014 Jul;134(1):127-34. Epub 2014 Mar 18 PubMed.

External Citations

  1. https://gatelabnu.shinyapps.io/ad_apoe_rna/

Further Reading

No Available Further Reading

Primary Papers

  1. Ramakrishnan A, Piehl N, Simonton B, Parikh M, Zhang Z, Teregulova V, van Olst L, Gate D. Epigenetic dysregulation in Alzheimer's disease peripheral immunity. Neuron. 2024 Apr 17;112(8):1235-1248.e5. Epub 2024 Feb 9 PubMed.

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