Research Models

APOE4 Knock-In (JAX)

Synonyms: APOE4 KI, APOE*4 KI

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Species: Mouse
Genes: APOE
Modification: APOE: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(SJL)-ApoEtm1.1(APOE*4)Adiuj/J

APOE4 knock-in mice express a humanized APOE4 allele from the endogenous ApoE locus. APOE was humanized by replacing mouse ApoE exons 2, 3, and most of exon 4, with human APOE4 sequence including exons 2, 3, 4 and a portion of the 3' UTR sequence.

Homozygotes are viable and fertile.

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Cognitive Impairment

No Data

  • Plaques
  • Tangles
  • Neuronal Loss
  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD

Plaques

No data.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

No data.

Gliosis

No data.

Changes in LTP/LTD

No data.

Cognitive Impairment

At 2 and 12 months of age, APOE4 KI mice perform similarly to wild-type mice in tests of locomotor activity, motor coordination, and working memory.

Last Updated: 30 Nov 2018

COMMENTS / QUESTIONS

No Available Comments

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Further Reading

No Available Further Reading

Therapeutics

PF-06852231

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Overview

Name: PF-06852231
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Pfizer

Background

PF-06852231 is a small-molecule cholinergic modulator. No preclinical information about this compound is published.

Findings

In July 2017, Pfizer began enrolling healthy volunteers for a safety, tolerability, and pharmacokinetics study of this compound at the company's clinical research unit in Brussels. In January 2018, Pfizer announced it was discontinuing its research and development work across neuroscience indications, and this compound was discontinued.

As of January 31, 2018, clinicaltrials.gov still showed this trial as enrolling; however, the Pfizer Pipeline of January 30, 2018, lists it as discontinued. 

Last Updated: 02 Feb 2018

Comments

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Further Reading

No Available Further Reading

Research Models

Trem2 KO (Colonna) x PS19

Synonyms: Trem2-/-PS19

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Species: Mouse
Genes: Trem2, MAPT
Modification: Trem2: Knock-Out; MAPT: Transgenic
Disease Relevance: Frontotemporal Dementia, Alzheimer's Disease
Strain Name: C57BL/6 -TREM2tm1cln; B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

No Data

  • Plaques
  • Tangles
  • Neuronal Loss
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

No data.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

No data.

Gliosis

Microgliosis and astrogliosis by 9 months (the earliest age studied).

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 01 Jul 2020

COMMENTS / QUESTIONS

No Available Comments

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Further Reading

No Available Further Reading

Research Models

Trem2 KO (Colonna) x 5XFAD

Synonyms: Trem2-/-5XFAD, mTrem2-/-5XFAD 

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Species: Mouse
Genes: Trem2, APP, PSEN1
Modification: Trem2: Knock-Out; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: C57BL/6 -TREM2tm1cln; B6.Cg-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmja

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

No Data

  • Tangles
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

Plaques present by 4 months, the earliest age studied.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

Loss of cortical layer V neurons by 8 months, the earliest age studied.

Gliosis

MIcrogliosis by 4 months, the earliest age studied.

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 20 Sep 2024

COMMENTS / QUESTIONS

  1. Neuroinflammatory mechanisms have emerged as an important feature and pathogenic event in Alzheimer’s disease. Recently, mutations in TREM2 have been identified as risk factors for the development of the sporadic type of this neurodegenerative disease. In this study, the Colonna group publishes the first profound analysis of microglial TREM2 function in murine AD models. One of the most intriguing findings of this study is that TREM2-deficient microglia seem to show an impaired reaction to Aβ deposition. Since TREM2-deficient 5xFAD mice showed an increase in the overall Aβ load in the hippocampus, this suggest that, at the investigated time point, TREM2 mediated mechanisms that restrict the deposition of Aβ. In keeping with this, TREM2 deficiency impaired microglial recruitment to the site of Aβ deposition. Importantly, the authors excluded, at least by in vitro experiments, that TREM2 deficiency affects microglia Aβ phagocytosis or degradation directly.

    Instead TREM2 seems to be involved in microglial survival mechanisms and TREM2 deficiency increased microglial apoptosis, possibly linked to restricted colony-stimulating factor 1 levels. Alternatively, TREM2-deficient cells may harm themselves by an increased release of TNFα, although several types of microglial cell death need to be considered (Kim and Li , 2013; Jung et al.  2005). Thus, TREM2-deficient microglia seem to not  survive the Aβ challenge and therefore fail to mount an appropriate clearance response, in line with previous findings showing that improving microglial phagocytosis in vivo can restrict Aβ deposition (Heneka et al., 2013).

    Another important finding of this study is that TREM2 is not activated by Aβ itself, as previously suggested, but by certain anionic membrane phospholipids, a a response that  was severely limited by the human R47H mutation, which has been linked to sporadic AD. Therefore, TREM2 expression at Aβ plaque sites (Frank et al., 2008; Lue et al., 2014) can be interpreted as an attempt to survive the local inflammatory and toxic milieu, a prerequisite to restrict Aβ accumulation by phagocytosis or release of degrading proteases.

    Overall this study further highlights the role of microglia in neurodegeneration and in particular in Alzheimer’s disease. Similar to previous studies, (e.g., Bradshaw et al., 2013) it points to microglial uptake and degradation of Aβ as an important method for restricting the peptide's accumulation. Given the plethora of GWAS-identified mutations that are potentially linked to immune function (Lambert et al.,  2013), it can be expected that further disease-relevant microglial functions will be discovered.

    Naturally, these findings fuel the hope of developing therapeutics that modify microglia functions. For this to be successful, we need to consider not only the different innate immune mechanisms, but the precise disease stage when they manifest.

    References:

    Kim SJ, Li J. Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia. Cell Death Dis. 2013 Jul 11;4:e716. PubMed.

    Jung DY, Lee H, Suk K. Pro-apoptotic activity of N-myc in activation-induced cell death of microglia. J Neurochem. 2005 Jul;94(1):249-56. PubMed.

    Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013 Jan 31;493(7434):674-8. Epub 2012 Dec 19 PubMed.

    Frank S, Burbach GJ, Bonin M, Walter M, Streit W, Bechmann I, Deller T. TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia. 2008 Oct;56(13):1438-47. PubMed.

    Lue LF, Schmitz CT, Serrano G, Sue LI, Beach TG, Walker DG. TREM2 Protein Expression Changes Correlate with Alzheimer's Disease Neurodegenerative Pathologies in Post-Mortem Temporal Cortices. Brain Pathol. 2014 Sep 3; PubMed.

    Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A, Rosenkrantz LL, Imboywa S, Lee M, Von Korff A, , Morris MC, Evans DA, Johnson K, Sperling RA, Schneider JA, Bennett DA, De Jager PL. CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nat Neurosci. 2013 Jul;16(7):848-50. PubMed.

    Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Morón FJ, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fiévet N, Huentelman MW, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuiness B, Larson EB, Green R, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, St George-Hyslop P, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossù P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Sanchez-Garcia F, Fox NC, Hardy J, Deniz Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Mancuso M, Matthews F, European Alzheimer's Disease Initiative (EADI), Genetic and Environmental Risk in Alzheimer's Disease, Alzheimer's Disease Genetic Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Moebus S, Mecocci P, Del Zompo M, Maier W, Hampel H, Pilotto A, Bullido M, Panza F, Caffarra P, Nacmias B, Gilbert JR, Mayhaus M, Lannefelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O'Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley TH Jr, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltuenen M, Martin ER, Schmidt R, Rujescu D, Wang LS, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nöthen MM, Graff C, Psaty BM, Jones L, Haines JL, Holmans PA, Lathrop M, Pericak-Vance MA, Launer LJ, Farrer LA, van Duijn CM, Van Broeckhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P, Wang J, Uitterlinden AG, Rivadeneira F, Koudstgaal PJ, Longstreth WT Jr, Becker JT, Kuller LH, Lumley T, Rice K, Garcia M, Aspelund T, Marksteiner JJ, Dal-Bianco P, Töglhofer AM, Freudenberger P, Ransmayr G, Benke T, Toeglhofer AM, Bressler J, Breteler MM, Fornage M, Hernández I, Rosende Roca M, Ana Mauleón M, Alegrat M, Ramírez-Lorca R, González-Perez A, Chapman J, Stretton A, Morgan A, Kehoe PG, Medway C, Lord J, Turton J, Hooper NM, Vardy E, Warren JD, Schott JM, Uphill J, Ryan N, Rossor M, Ben-Shlomo Y, Makrina D, Gkatzima O, Lupton M, Koutroumani M, Avramidou D, Germanou A, Jessen F, Riedel-Heller S, Dichgans M, Heun R, Kölsch H, Schürmann B, Herold C, Lacour A, Drichel D, Hoffman P, Kornhuber J, Gu W, Feulner T, van den Bussche H, Lawlor B, Lynch A, Mann D, Smith AD, Warden D, Wilcock G, Heuser I, Wiltgang J, Frölich L, Hüll M, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Jöckel KH, Klopp N, Wichmann HE, Dickson DW, Graff-Radford NR, Ma L, Bisceglio G, Fisher E, Warner N, Pickering-Brown S. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013 Dec;45(12):1452-8. Epub 2013 Oct 27 PubMed.

    View all comments by Michael Heneka

  2. The intriguing finding of the Wang et al. study is that lipids “activate” wild-type TREM2 and turn on NFAT signaling pathways whereas the R47H variant of TREM2, which is a risk allele for AD, PD, FTD, and ALS, is almost completely inactive in the NFAT reporter assay.

    NFAT singling regulates expression of pro-inflammatory cytokines TNF-α, IL-2, IFNg, etc. Thus, the charged lipids—presumably released from apoptotic neurons and coating the amyloid plaques—should activate WT microglia and stimulate the release of inflammatory cytokines, whereas those expressing R47H-TREM2 should not. By implication, WT-TREM2 should be proinflammatory and R47H-TREM2 should not promote inflammation in response to apoptotic cells. This seems to run counterintuitive to the common finding that increased inflammation is observed in the brains of patients with all four neurodegenerative diseases indicated above, and there is increasing evidence that chronic neuroinflammation is toxic to the brain function and initiates neurodegeneration.

    One thing to keep in mind is that the NFAT reporter assay was performed by overexpressing WT-TREM2 or R47H-TREM2 in 2B4 reporter T-cells. TREM2 has an extremely short cytoplasmic tail and is known to signal by binding another membrane protein ,DAP12/TYRO-BP, which possesses a longer cytoplasmic tail with an immunoreceptor tyrosine-based activation (ITAM) motif. From the information in the manuscript, it seems that Wang et al. transfected TREM2 alone and not TREM2+DAP12. Also unclear is whether 2B4 T-cells express endogenous DAP12 and if so, what the stoichiometry of overexpressed TREM2 to endogenous DAP12 is. Thus, at present it remains an open question whether the effects of R47H mutation on NFAT signaling reported here shed any light on the role of TREM2 in AD pathogenesis or are due to overexpression of the protein in a non-microglial cell line. Future studies will need to resolve the conundrum of how R47H-TREM2, which does not seem to promote inflammation, increases the risk for neurodegeneration.

    View all comments by Sanjay Pimplikar

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Further Reading

No Available Further Reading

Research Models

Trem2 KO (Colonna)

Synonyms: Trem2-/- (Colonna)

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Species: Mouse
Genes: Trem2
Modification: Trem2: Knock-Out
Disease Relevance: Nasu-Hakola Disease, Frontotemporal Dementia, Alzheimer's Disease
Strain Name: C57BL/6 -TREM2tm1cln

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Gliosis
  • Cognitive Impairment

No Data

  • Plaques
  • Tangles
  • Neuronal Loss
  • Synaptic Loss
  • Changes in LTP/LTD

Plaques

No data.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

No data.

Gliosis

No spontaneous gliosis, but impaired microglial response to injury.

Changes in LTP/LTD

No data.

Cognitive Impairment

Not observed.

Last Updated: 08 Mar 2018

COMMENTS / QUESTIONS

No Available Comments

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Further Reading

No Available Further Reading

Research Models

Trem2 KO (KOMP) x htau

Synonyms: hTau;Trem2−/−

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Species: Mouse
Genes: Mapt, MAPT, Trem2
Modification: Mapt: Knock-Out; MAPT: Transgenic; Trem2: Knock-Out
Disease Relevance: Nasu-Hakola Disease, Alzheimer's Disease, Frontotemporal Dementia
Strain Name: TREM2tm1(KOMP)Vlcg; B6.Cg-Mapttm1(EGFP)Klt Tg(MAPT)8cPdav/J

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Neuronal Loss

No Data

  • Plaques
  • Tangles
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

No data.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

Neuron loss not observed in cortex or hippocampal field CA3 at 6 months of age; later ages were not studied.

Gliosis

Microgliosis observed by 6 months, younger ages were not studied.

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 15 Apr 2024

COMMENTS / QUESTIONS

No Available Comments

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Further Reading

No Available Further Reading

Research Models

Trem2 KO (KOMP)

Synonyms: Trem2 −/− (KOMP)

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Species: Mouse
Genes: Trem2
Modification: Trem2: Knock-Out
Disease Relevance: Nasu-Hakola Disease, Frontotemporal Dementia, Alzheimer's Disease
Strain Name: Trem2tm1(KOMP)Vlcg

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Cognitive Impairment

No Data

  • Plaques
  • Tangles
  • Neuronal Loss
  • Gliosis
  • Synaptic Loss
  • Changes in LTP/LTD

Plaques

No data.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

No data.

Gliosis

No data.

Changes in LTP/LTD

No data.

Cognitive Impairment

At six months, mice perform normally in the open-field test, elevated plus maze, three-chamber social-interaction test, and contextual and cued fear-conditioning test.

Last Updated: 08 Mar 2018

COMMENTS / QUESTIONS

No Available Comments

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Further Reading

No Available Further Reading

Research Models

Trem2 KO (KOMP) x APPPS1

Synonyms: APPPS1;Trem2-/-

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Species: Mouse
Genes: Trem2, APP, PSEN1
Modification: Trem2: Knock-Out; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: TREM2tm1(KOMP)Vlcg; B6.Cg-Tg(Thy1-APPSw,Thy1-PSEN1*L166P)21Jckr

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

No Data

  • Tangles
  • Neuronal Loss
  • Synaptic Loss
  • Changes in LTP/LTD
  • Cognitive Impairment

Plaques

Plaques are observed by 2 months.

Tangles

No data.

Synaptic Loss

No data.

Neuronal Loss

No data.

Gliosis

Gliosis is observed by 2 months.

Changes in LTP/LTD

No data.

Cognitive Impairment

No data.

Last Updated: 16 Jul 2018

COMMENTS / QUESTIONS

No Available Comments

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Further Reading

No Available Further Reading

Research Models

Trem2 flox

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Species: Mouse
Genes: Trem2
Modification: Trem2: Knock-In
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease
Strain Name: B6(C3)-Trem2tm1c(EUCOMM)Wtsi/AdiujJ

Summary

These mice possess a floxed Trem2 allele. When bred to mice expressing Cre-recombinase driven by specific promoters, offspring can be used to study the conditional knockout of Trem2.

Heterozygotes are viable and fertile; viability and fertility in homozygous mice have not yet been reported.

Modification Details

Targeted insertion of LoxP sites flanking exons 2 and 3 of the mouse Trem2 gene.

Last Updated: 04 Oct 2018

COMMENTS / QUESTIONS

No Available Comments

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Further Reading

No Available Further Reading

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