Intrahippocampal administration of a domain antibody that binds aggregated amyloid-ß 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-ß (Aß) is neurotoxic, and we showed that intrahippocampal oligomeric Aß produces cognitive and metabolic dysfunction similar to that seen in DIO or diabetes. Moreover, animal models of DIO show elevated brain Aß, a hallmark of AD, suggesting that this may be one source of cognitive impairment in both conditions. METHODS: Intrahippocampal administration of a novel anti-Aß domain antibody for aggregated Aß, 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 Aß 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.