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Intrahippocampal administration of a domain antibody that binds aggregated amyloid-β reverses cognitive deficits produced by diet-induced obesity.

Abstract

BACKGROUND

The prevalence of high fat diets (HFD), diet-induced obesity (DIO) and Type 2 diabetes continues to increase, associated with cognitive impairment in both humans and rodent models. Mechanisms transducing these impairments remain largely unknown: one possibility is that a common mechanism may be involved in the cognitive impairment seen in obese and/or diabetic states and in dementia, specifically Alzheimer's disease (AD). DIO is well established as a risk factor for development of AD. Oligomeric amyloid-β (Aβ) is neurotoxic, and we showed that intrahippocampal oligomeric Aβ produces cognitive and metabolic dysfunction similar to that seen in DIO or diabetes. Moreover, animal models of DIO show elevated brain Aβ, a hallmark of AD, suggesting that this may be one source of cognitive impairment in both conditions.

METHODS

Intrahippocampal administration of a novel anti-Aβ domain antibody for aggregated Aβ, or a control domain antibody, to control or HFD-induced DIO rats. Spatial learning measured in a conditioned contextual fear (CCF) task after domain antibody treatment; postmortem, hippocampal NMDAR and AMPAR were measured.

RESULTS

DIO caused impairment in CCF, and this impairment was eliminated by intrahippocampal administration of the active domain antibody. Measurement of hippocampal proteins suggests that DIO causes dysregulation of hippocampal AMPA receptors, which is also reversed by acute domain antibody administration.

CONCLUSIONS

Our findings support the concept that oligomeric Aβ within the hippocampus of DIO animals may not only be a risk factor for development of AD but may also cause cognitive impairment before the development of dementia.

GENERAL SIGNIFICANCE AND INTEREST

Our work integrates the engineering of domain antibodies with conformational- and sequence-specificity for oligomeric amyloid beta with a clinically relevant model of diet-induced obesity in order to demonstrate not only the pervasive effects of obesity on several aspects of brain biochemistry and behavior, but also the bioengineering of a successful treatment against the long-term detrimental effects of a pre-diabetic state on the brain. We show for the first time that cognitive impairment linked to obesity and/or insulin resistance may be due to early accumulation of oligomeric beta-amyloid in the brain, and hence may represent a pre-Alzheimer's state.

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  • Authors+Show Affiliations

    ,

    Behavioral Neuroscience, University at Albany, Albany, NY, United States; Center for Neuroscience Research, University at Albany, Albany, NY, United States.

    ,

    Hofstra North Shore-Long Island School of Medicine, Hofstra University, Hempstead, NY, United States.

    ,

    University of Virginia School of Medicine, Charlottesville, VA, United States.

    ,

    Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY, United States.

    ,

    Center for Biotechnology and Interdisciplinary Studies, Isermann Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY, United States.

    ,

    Center for Biotechnology and Interdisciplinary Studies, Isermann Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY, United States.

    Behavioral Neuroscience, University at Albany, Albany, NY, United States; Center for Neuroscience Research, University at Albany, Albany, NY, United States; Biological Sciences, University at Albany, Albany, NY, United States. Electronic address: emcnay@albany.edu.

    Source

    Biochimica et biophysica acta 1860:6 2016 Jun pg 1291-8

    MeSH

    Amyloid beta-Peptides
    Animals
    Antibodies
    Cognition Disorders
    Diet, High-Fat
    Hippocampus
    Male
    Obesity
    Protein Aggregates
    Rats
    Rats, Sprague-Dawley
    Receptors, AMPA

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    26970498

    Citation

    Osborne, Danielle M., et al. "Intrahippocampal Administration of a Domain Antibody That Binds Aggregated Amyloid-β Reverses Cognitive Deficits Produced By Diet-induced Obesity." Biochimica Et Biophysica Acta, vol. 1860, no. 6, 2016, pp. 1291-8.
    Osborne DM, Fitzgerald DP, O'Leary KE, et al. Intrahippocampal administration of a domain antibody that binds aggregated amyloid-β reverses cognitive deficits produced by diet-induced obesity. Biochim Biophys Acta. 2016;1860(6):1291-8.
    Osborne, D. M., Fitzgerald, D. P., O'Leary, K. E., Anderson, B. M., Lee, C. C., Tessier, P. M., & McNay, E. C. (2016). Intrahippocampal administration of a domain antibody that binds aggregated amyloid-β reverses cognitive deficits produced by diet-induced obesity. Biochimica Et Biophysica Acta, 1860(6), pp. 1291-8. doi:10.1016/j.bbagen.2016.03.005.
    Osborne DM, et al. Intrahippocampal Administration of a Domain Antibody That Binds Aggregated Amyloid-β Reverses Cognitive Deficits Produced By Diet-induced Obesity. Biochim Biophys Acta. 2016;1860(6):1291-8. PubMed PMID: 26970498.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Intrahippocampal administration of a domain antibody that binds aggregated amyloid-β reverses cognitive deficits produced by diet-induced obesity. AU - Osborne,Danielle M, AU - Fitzgerald,Dennis P, AU - O'Leary,Kelsey E, AU - Anderson,Brian M, AU - Lee,Christine C, AU - Tessier,Peter M, AU - McNay,Ewan C, Y1 - 2016/03/10/ PY - 2015/11/16/received PY - 2016/02/20/revised PY - 2016/03/06/accepted PY - 2016/3/13/entrez PY - 2016/3/13/pubmed PY - 2016/8/2/medline KW - AMPA KW - Amyloid KW - Antibody KW - Cognition KW - Diet KW - High-Fat KW - Obesity SP - 1291 EP - 8 JF - Biochimica et biophysica acta JO - Biochim. Biophys. Acta VL - 1860 IS - 6 N2 - BACKGROUND: The prevalence of high fat diets (HFD), diet-induced obesity (DIO) and Type 2 diabetes continues to increase, associated with cognitive impairment in both humans and rodent models. Mechanisms transducing these impairments remain largely unknown: one possibility is that a common mechanism may be involved in the cognitive impairment seen in obese and/or diabetic states and in dementia, specifically Alzheimer's disease (AD). DIO is well established as a risk factor for development of AD. Oligomeric amyloid-β (Aβ) is neurotoxic, and we showed that intrahippocampal oligomeric Aβ produces cognitive and metabolic dysfunction similar to that seen in DIO or diabetes. Moreover, animal models of DIO show elevated brain Aβ, a hallmark of AD, suggesting that this may be one source of cognitive impairment in both conditions. METHODS: Intrahippocampal administration of a novel anti-Aβ domain antibody for aggregated Aβ, or a control domain antibody, to control or HFD-induced DIO rats. Spatial learning measured in a conditioned contextual fear (CCF) task after domain antibody treatment; postmortem, hippocampal NMDAR and AMPAR were measured. RESULTS: DIO caused impairment in CCF, and this impairment was eliminated by intrahippocampal administration of the active domain antibody. Measurement of hippocampal proteins suggests that DIO causes dysregulation of hippocampal AMPA receptors, which is also reversed by acute domain antibody administration. CONCLUSIONS: Our findings support the concept that oligomeric Aβ within the hippocampus of DIO animals may not only be a risk factor for development of AD but may also cause cognitive impairment before the development of dementia. GENERAL SIGNIFICANCE AND INTEREST: Our work integrates the engineering of domain antibodies with conformational- and sequence-specificity for oligomeric amyloid beta with a clinically relevant model of diet-induced obesity in order to demonstrate not only the pervasive effects of obesity on several aspects of brain biochemistry and behavior, but also the bioengineering of a successful treatment against the long-term detrimental effects of a pre-diabetic state on the brain. We show for the first time that cognitive impairment linked to obesity and/or insulin resistance may be due to early accumulation of oligomeric beta-amyloid in the brain, and hence may represent a pre-Alzheimer's state. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/26970498/Intrahippocampal_administration_of_a_domain_antibody_that_binds_aggregated_amyloid_β_reverses_cognitive_deficits_produced_by_diet_induced_obesity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-4165(16)30060-5 DB - PRIME DP - Unbound Medicine ER -