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.

Obesity Prevents S-Adenosylmethionine-Mediated Improvements in Age-Related Peripheral and Hippocampal Outcomes

“…The body operates poorly under obese conditions. In particular, when compounded by age, hippocampal functions can become impaired [ 27 , 28 ]. We looked at age-related markers of peripheral and hippocampal health, with or without the addition of long-term obesity, and determined that SAMe supplementation is beneficial to aged mice across all measurements, but the positive effects of SAMe were diminished with obesity.…”

The Involvement of Peripheral and Brain Insulin Resistance in Late Onset Alzheimer’s Dementia

“…In this point, an important question arises: what is the molecular link between diet, T2DM and cognitive impairment? In this regard, Osborne et al (2016) reported that intrahippocampal infusion of an Aβ33–42 gamma antibody reversed cognitive impairment in rats with HFD-related cognitive loss. Hence, these results stressed the role of soluble Aβ in obesity-mediated cognitive loss and they are in agreement with previous studies hypothesizing that diffusible Aβ oligomers are responsible for neural dysfunction leading to AD (Walsh et al, 2005; Tarasoff-Conway et al, 2015; Xia et al, 2016; Bu et al, 2018; Hurtado-Puerto et al, 2018).…”

The Neuroprotective Effects of Policosanol on Learning and Memory Impairment in a Male Rat Model of Alzheimer's Disease

“…It has been shown AD is highly observed in states, in which the consumption of diets high in and calorie is high (Martin et al, 2014). Diet-induced obesity (DIO) is linked to cognitive defect and pathological alterations similar to changes observed in AD (Heyward et al, 2012;Yang et al, 2013;Boitard et al, 2014;Osborne et al, 2016). Although eating a highfat diet (HFD) affects AD-associated pathology in different animal models and conditions (Grant, 1999;Grillo et al, 2011;Soares et al, 2013;Hsu and Kanoski, 2014), the mechanisms linking risk factors to AD pathogenesis are not still clear (Thériault et al, 2016).…”