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Intraneuronal Aβ detection in 5xFAD mice by a new Aβ-specific antibody.
Mol Neurodegener 2012; 7:8MN

Abstract

BACKGROUND

The form(s) of amyloid-β peptide (Aβ) associated with the pathology characteristic of Alzheimer's disease (AD) remains unclear. In particular, the neurotoxicity of intraneuronal Aβ accumulation is an issue of considerable controversy; even the existence of Aβ deposits within neurons has recently been challenged by Winton and co-workers. These authors purport that it is actually intraneuronal APP that is being detected by antibodies thought to be specific for Aβ. To further address this issue, an anti-Aβ antibody was developed (MOAB-2) that specifically detects Aβ, but not APP. This antibody allows for the further evaluation of the early accumulation of intraneuronal Aβ in transgenic mice with increased levels of human Aβ in 5xFAD and 3xTg mice.

RESULTS

MOAB-2 (mouse IgG2b) is a pan-specific, high-titer antibody to Aβ residues 1-4 as demonstrated by biochemical and immunohistochemical analyses (IHC), particularly compared to 6E10 (a commonly used commercial antibody to Aβ residues 3-8). MOAB-2 did not detect APP or APP-CTFs in cell culture media/lysates (HEK-APPSwe or HEK-APPSwe/BACE1) or in brain homogenates from transgenic mice expressing 5 familial AD (FAD) mutation (5xFAD mice). Using IHC on 5xFAD brain tissue, MOAB-2 immunoreactivity co-localized with C-terminal antibodies specific for Aβ40 and Aβ42. MOAB-2 did not co-localize with either N- or C-terminal antibodies to APP. In addition, no MOAB-2-immunoreactivity was observed in the brains of 5xFAD/BACE-/- mice, although significant amounts of APP were detected by N- and C-terminal antibodies to APP, as well as by 6E10. In both 5xFAD and 3xTg mouse brain tissue, MOAB-2 co-localized with cathepsin-D, a marker for acidic organelles, further evidence for intraneuronal Aβ, distinct from Aβ associated with the cell membrane. MOAB-2 demonstrated strong intraneuronal and extra-cellular immunoreactivity in 5xFAD and 3xTg mouse brain tissues.

CONCLUSIONS

Both intraneuronal Aβ accumulation and extracellular Aβ deposition was demonstrated in 5xFAD mice and 3xTg mice with MOAB-2, an antibody that will help differentiate intracellular Aβ from APP. However, further investigation is required to determine whether a molecular mechanism links the presence of intraneuronal Aβ with neurotoxicity. As well, understanding the relevance of these observations to human AD patients is critical.

Authors+Show Affiliations

Department of Anatomy and Cell Biology, University of Illinois at Chicago, IL 60612, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22423893

Citation

Youmans, Katherine L., et al. "Intraneuronal Aβ Detection in 5xFAD Mice By a New Aβ-specific Antibody." Molecular Neurodegeneration, vol. 7, 2012, p. 8.
Youmans KL, Tai LM, Kanekiyo T, et al. Intraneuronal Aβ detection in 5xFAD mice by a new Aβ-specific antibody. Mol Neurodegener. 2012;7:8.
Youmans, K. L., Tai, L. M., Kanekiyo, T., Stine, W. B., Michon, S. C., Nwabuisi-Heath, E., ... LaDu, M. J. (2012). Intraneuronal Aβ detection in 5xFAD mice by a new Aβ-specific antibody. Molecular Neurodegeneration, 7, p. 8. doi:10.1186/1750-1326-7-8.
Youmans KL, et al. Intraneuronal Aβ Detection in 5xFAD Mice By a New Aβ-specific Antibody. Mol Neurodegener. 2012 Mar 16;7:8. PubMed PMID: 22423893.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intraneuronal Aβ detection in 5xFAD mice by a new Aβ-specific antibody. AU - Youmans,Katherine L, AU - Tai,Leon M, AU - Kanekiyo,Takahisa, AU - Stine,W Blaine,Jr AU - Michon,Sara-Claude, AU - Nwabuisi-Heath,Evelyn, AU - Manelli,Arlene M, AU - Fu,Yifan, AU - Riordan,Sean, AU - Eimer,William A, AU - Binder,Lester, AU - Bu,Guojun, AU - Yu,Chunjiang, AU - Hartley,Dean M, AU - LaDu,Mary Jo, Y1 - 2012/03/16/ PY - 2011/12/04/received PY - 2012/03/16/accepted PY - 2012/3/20/entrez PY - 2012/3/20/pubmed PY - 2012/8/31/medline SP - 8 EP - 8 JF - Molecular neurodegeneration JO - Mol Neurodegener VL - 7 N2 - BACKGROUND: The form(s) of amyloid-β peptide (Aβ) associated with the pathology characteristic of Alzheimer's disease (AD) remains unclear. In particular, the neurotoxicity of intraneuronal Aβ accumulation is an issue of considerable controversy; even the existence of Aβ deposits within neurons has recently been challenged by Winton and co-workers. These authors purport that it is actually intraneuronal APP that is being detected by antibodies thought to be specific for Aβ. To further address this issue, an anti-Aβ antibody was developed (MOAB-2) that specifically detects Aβ, but not APP. This antibody allows for the further evaluation of the early accumulation of intraneuronal Aβ in transgenic mice with increased levels of human Aβ in 5xFAD and 3xTg mice. RESULTS: MOAB-2 (mouse IgG2b) is a pan-specific, high-titer antibody to Aβ residues 1-4 as demonstrated by biochemical and immunohistochemical analyses (IHC), particularly compared to 6E10 (a commonly used commercial antibody to Aβ residues 3-8). MOAB-2 did not detect APP or APP-CTFs in cell culture media/lysates (HEK-APPSwe or HEK-APPSwe/BACE1) or in brain homogenates from transgenic mice expressing 5 familial AD (FAD) mutation (5xFAD mice). Using IHC on 5xFAD brain tissue, MOAB-2 immunoreactivity co-localized with C-terminal antibodies specific for Aβ40 and Aβ42. MOAB-2 did not co-localize with either N- or C-terminal antibodies to APP. In addition, no MOAB-2-immunoreactivity was observed in the brains of 5xFAD/BACE-/- mice, although significant amounts of APP were detected by N- and C-terminal antibodies to APP, as well as by 6E10. In both 5xFAD and 3xTg mouse brain tissue, MOAB-2 co-localized with cathepsin-D, a marker for acidic organelles, further evidence for intraneuronal Aβ, distinct from Aβ associated with the cell membrane. MOAB-2 demonstrated strong intraneuronal and extra-cellular immunoreactivity in 5xFAD and 3xTg mouse brain tissues. CONCLUSIONS: Both intraneuronal Aβ accumulation and extracellular Aβ deposition was demonstrated in 5xFAD mice and 3xTg mice with MOAB-2, an antibody that will help differentiate intracellular Aβ from APP. However, further investigation is required to determine whether a molecular mechanism links the presence of intraneuronal Aβ with neurotoxicity. As well, understanding the relevance of these observations to human AD patients is critical. SN - 1750-1326 UR - https://www.unboundmedicine.com/medline/citation/22423893/Intraneuronal_Aβ_detection_in_5xFAD_mice_by_a_new_Aβ_specific_antibody_ L2 - https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-7-8 DB - PRIME DP - Unbound Medicine ER -