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Article ; Online: A modified Barnes maze for an accurate assessment of spatial learning in mice.

Illouz, Tomer / Madar, Ravit / Okun, Eitan

2020 Volume 334, Page(s) 108579

Abstract: Background: The Morris water maze (MWM) and the Barnes maze (BM) are among the most widely-used paradigms for assessing spatial learning in rodents, with specific advantages and disadvantages for each apparatus. Compared with the intense water-related ... ...

Abstract	Background: The Morris water maze (MWM) and the Barnes maze (BM) are among the most widely-used paradigms for assessing spatial learning in rodents, with specific advantages and disadvantages for each apparatus. Compared with the intense water-related stress exerted during the MWM, the BM exhibits a milder light-induced stress, while suffering from biasing animals towards non-spatial strategies such as serial search, a heuristic non-spatial search strategy. To overcome this problem, we have developed a modified Barnes maze (MBM) apparatus that recapitulates natural environments more accurately without inducing undesirable exploration strategy bias. New method: Apparatus. A circular 122 cm-wide table with 40 randomly placed holes. One target hole is leading to an escape chamber. Task. Three target locations were examined, varying in their distance from the center. C57BL6/j male mice were given three trials per day to find the target. Following acquisition, a probe test was performed by removing the escape chamber. Results: Spatial-encoding-depended reduction in latency to reach the target was observed, along with improvement in path efficiency with test progress. Mice tested with peripheral and distal targets outperformed mice tested with a central target. A robust exploration pattern was identified in the probe test. Comparison with existing method: The MBM mimics natural environment to a higher degree of accuracy than the BM, without eliciting bias towards non-spatial searching strategies. Conclusions: Spatial learning in the MBM is a target-location sensitive process, providing flexibility in task difficulty. Along with overcoming biases towards non-spatial strategies, the MBM represents an improvement over the well-validated BM.
Language	English
Publishing date	2020-01-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	282721-9
ISSN	1872-678X ; 0165-0270
ISSN (online)	1872-678X
ISSN	0165-0270
DOI	10.1016/j.jneumeth.2020.108579
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Article ; Online: Induction of an effective anti-Amyloid-β humoral response in aged mice.

Illouz, Tomer / Madar, Ravit / Hirsh, Tamir / Biragyn, Arya / Okun, Eitan

Vaccine

2021 Volume 39, Issue 34, Page(s) 4817–4829

Abstract: Aging-related decline in immune functions, termed immunosenescence, is a primary cause of reduced protective responses to vaccines in the elderly, due to impaired induction of cellular and humoral responses to new antigens (Ag), especially if the ... ...

Abstract	Aging-related decline in immune functions, termed immunosenescence, is a primary cause of reduced protective responses to vaccines in the elderly, due to impaired induction of cellular and humoral responses to new antigens (Ag), especially if the response is T cell dependent. The result is a more severe morbidity following infections, more prolonged and frequent hospitalization, and a higher mortality rate than in the general population. Therefore, there is an increasing need to develop vaccination strategies that overcome immunosenescence, especially for aging-related diseases such as Alzheimer's disease (AD). Here we report a new vaccination strategy harnessing memory-based immunity, which is less affected by aging. We found that aged C57BL/6 and 5xFAD mice exhibit a dramatic reduction in anti-Amyloid-β (Aβ) antibody (Ab) production. We aimed to reverse this process by inducing memory response at a young age. To this end, young mice were primed with the vaccine carrier Hepatitis B surface antigen (HBsAg). At an advanced age, these mice were immunized with an Aβ
MeSH term(s)	Aged ; Alzheimer Disease/prevention & control ; Amyloid beta-Peptides ; Animals ; Disease Models, Animal ; Hepatitis B Vaccines ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Peptide Fragments
Chemical Substances	Amyloid beta-Peptides ; Hepatitis B Vaccines ; Peptide Fragments
Language	English
Publishing date	2021-07-20
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2021.07.023
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Article ; Online: Virtual reality-based training and pre-operative planning for head and neck sentinel lymph node biopsy.

Feinmesser, Gilad / Yogev, David / Goldberg, Tomer / Parmet, Yisrael / Illouz, Shay / Vazgovsky, Oliana / Eshet, Yael / Tejman-Yarden, Shai / Alon, Eran

American journal of otolaryngology

2023 Volume 44, Issue 6, Page(s) 103976

Abstract: Objective: Sentinel lymph node biopsy (SLNB) is crucial for managing head and neck skin cancer. However, variable lymphatic drainage can complicate SLN detection when using Single-Photon Emission Computed Tomography (SPECT) or lymphoscintigraphy. ... ...

Abstract	Objective: Sentinel lymph node biopsy (SLNB) is crucial for managing head and neck skin cancer. However, variable lymphatic drainage can complicate SLN detection when using Single-Photon Emission Computed Tomography (SPECT) or lymphoscintigraphy. Virtual Reality (VR) can contribute to pre-operative planning by simulating a realistic 3D model, which improves orientation. VR can also facilitate real-patient training outside the operating room. This study explored using a VR platform for pre-operative planning in head and neck skin cancer patients undergoing SLNBs and assessed its value for residential training. Materials and methods: In this prospective technology pilot study, attending surgeons and residents who performed 21 SLNB operations on patients with head and neck skin cancers (81% males, mean age 69.2 ± 11.3) used a VR simulation model based on each patient's pre-operative SPECT scan to examine patient-specific anatomy. After surgery, they completed a questionnaire on the efficiency of the VR simulation as a pre-operative planning tool and training device for residents. Results: The attending surgeons rated the VR model's accuracy at 8.3 ± 1.6 out of 10. Three-quarters (76%) of residents reported increased confidence after using VR. The physicians rated the platform's contribution to residents' training at 7.4 ± 2.1 to 8.9 ± 1.3 out of 10. Conclusion: A VR SLNB simulation can accurately portray marked sentinel lymph nodes. It was rated high as a surgical planning and teaching tool among attending surgeons and residents alike and may play a role in pre-operative planning and resident training. Further studies are needed to explore its applications in practice.
MeSH term(s)	Male ; Humans ; Middle Aged ; Aged ; Aged, 80 and over ; Female ; Sentinel Lymph Node Biopsy/methods ; Skin Neoplasms/pathology ; Melanoma/pathology ; Prospective Studies ; Pilot Projects ; Lymph Nodes/pathology ; Head and Neck Neoplasms/diagnostic imaging ; Head and Neck Neoplasms/surgery ; Head and Neck Neoplasms/pathology ; Virtual Reality
Language	English
Publishing date	2023-07-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	604541-8
ISSN	1532-818X ; 0196-0709
ISSN (online)	1532-818X
ISSN	0196-0709
DOI	10.1016/j.amjoto.2023.103976
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Article: Induction of an effective anti-Amyloid-β humoral response in aged mice

Illouz, Tomer / Madar, Ravit / Hirsh, Tamir / Biragyn, Arya / Okun, Eitan

Vaccine. 2021 Aug. 09, v. 39, no. 34

2021

Abstract	Aging-related decline in immune functions, termed immunosenescence, is a primary cause of reduced protective responses to vaccines in the elderly, due to impaired induction of cellular and humoral responses to new antigens (Ag), especially if the response is T cell dependent. The result is a more severe morbidity following infections, more prolonged and frequent hospitalization, and a higher mortality rate than in the general population. Therefore, there is an increasing need to develop vaccination strategies that overcome immunosenescence, especially for aging-related diseases such as Alzheimer’s disease (AD). Here we report a new vaccination strategy harnessing memory-based immunity, which is less affected by aging. We found that aged C57BL/6 and 5xFAD mice exhibit a dramatic reduction in anti-Amyloid-β (Aβ) antibody (Ab) production. We aimed to reverse this process by inducing memory response at a young age. To this end, young mice were primed with the vaccine carrier Hepatitis B surface antigen (HBsAg). At an advanced age, these mice were immunized with an Aβ₁₋₁₁ fused to HBsAg. This vaccination scheme elicited a markedly higher Aβ-specific antibody titer than vaccinating aged unprimed mice with the same construct. Importantly, this vaccine strategy more efficiently reduced cerebral Aβ levels and altered microglial phenotype. Overall, we provide evidence that priming with an exogenous Ag carrier can overcome impaired humoral responses to self-antigens in the elderly, paving the route for a potent immunotherapy to AD.
Keywords	T-lymphocytes ; antibodies ; decline ; elderly ; hepatitis B antigens ; humoral immunity ; memory ; morbidity ; mortality ; phenotype ; vaccination ; vaccines
Language	English
Dates of publication	2021-0809
Size	p. 4817-4829.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2021.07.023
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Zs.MO 458: Show issues

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Article ; Online: Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis.

Illouz, Tomer / Nicola, Raneen / Ben-Shushan, Linoy / Madar, Ravit / Biragyn, Arya / Okun, Eitan

Communications biology

2021 Volume 4, Issue 1, Page(s) 329

Abstract: Maternal antibodies (MAbs) protect against infections in immunologically-immature neonates. Maternally transferred immunity may also be harnessed to target diseases associated with endogenous protein misfolding and aggregation, such as Alzheimer's ... ...

Abstract	Maternal antibodies (MAbs) protect against infections in immunologically-immature neonates. Maternally transferred immunity may also be harnessed to target diseases associated with endogenous protein misfolding and aggregation, such as Alzheimer's disease (AD) and AD-pathology in Down syndrome (DS). While familial early-onset AD (fEOAD) is associated with autosomal dominant mutations in the APP, PSEN1,2 genes, promoting cerebral Amyloid-β (Aβ) deposition, DS features a life-long overexpression of the APP and DYRK1A genes, leading to a cognitive decline mediated by Aβ overproduction and tau hyperphosphorylation. Although no prenatal screening for fEOAD-related mutations is in clinical practice, DS can be diagnosed in utero. We hypothesized that anti-Aβ MAbs might promote the removal of early Aβ accumulation in the central nervous system of human APP-expressing mice. To this end, a DNA-vaccine expressing Aβ
MeSH term(s)	Alzheimer Disease/enzymology ; Alzheimer Disease/immunology ; Alzheimer Disease/pathology ; Alzheimer Disease/prevention & control ; Alzheimer Vaccines/administration & dosage ; Alzheimer Vaccines/immunology ; Amyloid beta-Peptides/administration & dosage ; Amyloid beta-Peptides/immunology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Antibodies/immunology ; Antibodies/metabolism ; Behavior, Animal ; Brain/enzymology ; Brain/immunology ; Brain/pathology ; Cognition ; Disease Models, Animal ; Female ; Immunization ; Male ; Memory ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/enzymology ; Microglia/immunology ; Microglia/pathology ; Peptide Fragments/administration & dosage ; Peptide Fragments/immunology ; Phagocytosis ; Phenotype ; Plaque, Amyloid ; Receptors, IgG/metabolism ; Signal Transduction ; Syk Kinase/metabolism ; Vaccines, DNA/administration & dosage ; Vaccines, DNA/immunology ; Mice
Chemical Substances	APP protein, human ; Alzheimer Vaccines ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Antibodies ; Fcgr1 protein, mouse ; Peptide Fragments ; Receptors, IgG ; Vaccines, DNA ; amyloid beta-protein (1-11) ; Syk Kinase (EC 2.7.10.2) ; Syk protein, mouse (EC 2.7.10.2)
Language	English
Publishing date	2021-03-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-021-01851-6
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: No ECSIT-stential evidence for a link with Alzheimer's disease yet (retrospective on DOI 10.1002/bies.201100193).

Illouz, Tomer / Okun, Eitan

BioEssays : news and reviews in molecular, cellular and developmental biology

2015 Volume 37, Issue 1, Page(s) 5

MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Humans ; Protein Interaction Maps ; Reactive Oxygen Species/metabolism ; Reproducibility of Results ; Signal Transduction
Chemical Substances	Adaptor Proteins, Signal Transducing ; Amyloid beta-Peptides ; Reactive Oxygen Species
Language	English
Publishing date	2015-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	50140-2
ISSN	1521-1878 ; 0265-9247
ISSN (online)	1521-1878
ISSN	0265-9247
DOI	10.1002/bies.201400179
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Article ; Online: Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis

Tomer Illouz / Raneen Nicola / Linoy Ben-Shushan / Ravit Madar / Arya Biragyn / Eitan Okun

Communications Biology, Vol 4, Iss 1, Pp 1-

2021 Volume 19

Abstract: Illouz et al vaccinated wildtype female mice against human Amyloid-β (Aβ) prior to them being bred ...

Abstract	Illouz et al vaccinated wildtype female mice against human Amyloid-β (Aβ) prior to them being bred with 5xFAD males, which model Aβ deposition, as occurs in Alzheimer’s Disease (AD) and Down’s syndrome (DS). The resultant offspring had reduced cortical Aβ levels and milder memory deficits, up to 4 months after antibodies were no longer detectable, due to a long term shift in microglial phenotype. This study demonstrates that maternal immunization can alleviate cognitive decline and pathology associated with AD and DS.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Restoring microglial and astroglial homeostasis using DNA immunization in a Down Syndrome mouse model.

Illouz, Tomer / Madar, Ravit / Biragyn, Arya / Okun, Eitan

Brain, behavior, and immunity

2018 Volume 75, Page(s) 163–180

Abstract: Down Syndrome (DS), the most common cause of genetic intellectual disability, is characterized by over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by ...

Abstract	Down Syndrome (DS), the most common cause of genetic intellectual disability, is characterized by over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation as early as the age of 40. In this study, we used the Ts65Dn mouse model of DS to evaluate the beneficial effect of a DNA vaccination against the Aβ
MeSH term(s)	Alzheimer Disease/pathology ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/immunology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Astrocytes/immunology ; Astrocytes/metabolism ; Brain/metabolism ; DNA/immunology ; Disease Models, Animal ; Down Syndrome/immunology ; Down Syndrome/metabolism ; Hippocampus/metabolism ; Immunization/methods ; Male ; Mice ; Mice, Transgenic ; Microglia/immunology ; Microglia/metabolism ; Phenotype ; Phosphorylation ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Protein-Tyrosine Kinases/genetics ; Protein-Tyrosine Kinases/metabolism ; tau Proteins ; Dyrk Kinases
Chemical Substances	APP protein, human ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; tau Proteins ; DNA (9007-49-2) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2018-10-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639219-2
ISSN	1090-2139 ; 0889-1591
ISSN (online)	1090-2139
ISSN	0889-1591
DOI	10.1016/j.bbi.2018.10.004
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Article: Disease-associated astrocyte epigenetic memory promotes CNS pathology.

Lee, Hong-Gyun / Rone, Joseph M / Li, Zhaorong / Akl, Camilo Faust / Shin, Seung Won / Lee, Joon-Hyuk / Flausino, Lucas E / Pernin, Florian / Chao, Chun-Cheih / Kleemann, Kilian L / Srun, Lena / Illouz, Tomer / Giovannoni, Federico / Charabati, Marc / Sanmarco, Liliana M / Kenison, Jessica E / Piester, Gavin / Zandee, Stephanie E J / Antel, Jack /

Rothhammer, Veit / Wheeler, Michael A / Prat, Alexandre / Clark, Iain C / Quintana, Francisco J

bioRxiv : the preprint server for biology

2024

Abstract: Astrocytes play important roles in the central nervous system (CNS) physiology and pathology. Indeed, astrocyte subsets defined by specific transcriptional activation states contribute to the pathology of neurologic diseases, including multiple sclerosis ...

Abstract	Astrocytes play important roles in the central nervous system (CNS) physiology and pathology. Indeed, astrocyte subsets defined by specific transcriptional activation states contribute to the pathology of neurologic diseases, including multiple sclerosis (MS) and its pre-clinical model experimental autoimmune encephalomyelitis (EAE)
Language	English
Publishing date	2024-01-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.04.574196
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Article ; Online: A protocol for quantitative analysis of murine and human amyloid-β

Illouz, Tomer / Madar, Ravit / Griffioen, Kathleen / Okun, Eitan

Journal of neuroscience methods

2017 Volume 291, Page(s) 28–35

Abstract: Background: Amyloid-β (Aβ), a hallmark of Alzheimer's disease (AD), has long been a focus of basic and translation research in AD. Quantification and dissociation of the Aβ fractions in their soluble and insoluble forms, is a key factor in numerous AD ... ...

Abstract	Background: Amyloid-β (Aβ), a hallmark of Alzheimer's disease (AD), has long been a focus of basic and translation research in AD. Quantification and dissociation of the Aβ fractions in their soluble and insoluble forms, is a key factor in numerous AD studies. New method: Here we provide a generalized sandwich-enzyme-linked-immuno-sorbent-assay (sELISA) protocol for quantification of human and murine Aβ Results: We have validated the levels of soluble and insoluble Aβ Comparison with existing methods: Several methodologies have been proposed for the high throughput measure of Aβ, including HPLC-mass-spectrometry, micro-immunoelectrodes, immunoprecipitation and ELISA. Although commercial sELISA kits are widely used, herein, we describe a more accessible and cost-effective in-house protocol enabling to measure either human or murine, soluble and insoluble Aβ Conclusions: We provide a streamlined and accessible protocol for the assessment of soluble and insoluble Aβ
MeSH term(s)	Amyloid beta-Peptides/analysis ; Amyloid beta-Peptides/metabolism ; Animals ; Blood Chemical Analysis/methods ; Brain Chemistry ; Cerebral Cortex/metabolism ; Disease Models, Animal ; Down Syndrome/metabolism ; Enzyme-Linked Immunosorbent Assay/methods ; Hippocampus/metabolism ; Humans ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Peptide Fragments/analysis ; Peptide Fragments/metabolism ; Reproducibility of Results
Chemical Substances	Amyloid beta-Peptides ; Peptide Fragments ; amyloid beta-protein (1-40) ; amyloid beta-protein (1-42)
Language	English
Publishing date	2017--01
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	282721-9
ISSN	1872-678X ; 0165-0270
ISSN (online)	1872-678X
ISSN	0165-0270
DOI	10.1016/j.jneumeth.2017.07.022
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