IVIg protects the 3xTg-AD mouse model of Alzheimer’s disease from memory deficit and Aβ pathology

Abstract

BackgroundIntravenous immunoglobulin (IVIg) is currently in clinical study for Alzheimer’s disease (AD). However, preclinical investigations are required to better understand AD-relevant outcomes of IVIg treatment and develop replacement therapies in case of unsustainable supply.MethodsWe investigated the effects of IVIg in the 3xTg-AD mouse model, which reproduces both Aβ and tau pathologies. Mice were injected twice weekly with 1.5 g/kg IVIg for 1 or 3 months.ResultsIVIg induced a modest but significant improvement in memory in the novel object recognition test and attenuated anxiety-like behavior in 3xTg-AD mice. We observed a correction of immunologic defects present in 3xTg-AD mice (−22% CD4/CD8 blood ratio; −17% IL-5/IL-10 ratio in the cortex) and a modulation of CX3CR1+ cell population (−13% in the bone marrow). IVIg treatment led to limited effects on tau pathology but resulted in a 22% reduction of the soluble Aβ42/Aβ40 ratio and a 60% decrease in concentrations of 56 kDa Aβ oligomers (Aβ*56).ConclusionThe memory-enhancing effect of IVIg reported here suggests that Aβ oligomers, effector T cells and the fractalkine pathway are potential pharmacological targets of IVIg in AD.

ELISA measurement of specific antibodies to phosphorylated tau in intravenous immunoglobulin products

“…Conflicting results have been published regarding IVIG's effects on NFTs in the 3xTgAD transgenic mouse model of AD, which develops both plaques and NFTs. Gammagard administration to these mice was reported to result in a small (~15%) but statistically significant decrease in hippocampal NFTs [17], but no reduction in tau pathology was found when Gamunex was administered [18]. These findings contrast with neuroprotective effects obtained when tauopathy mice were treated with monoclonal anti-pTau antibodies [6,7].…”

Cognitive-Enhancing Effects of a Polyphenols-Rich Extract from Fruits without Changes in Neuropathology in an Animal Model of Alzheimer’s Disease

“…No effect on synaptic proteins was observed either, including drebrin, whose levels are decreased in AD [69,70]. We previously reported that the drebrin loss in the brain cortex of 3xTg-AD was minimal compared to NonTg mice [35,46], while no difference was observed in synaptophysin and SNAP-25 levels between NonTg and 3xTg-AD mice [35,37,46]. In contrast, a previous study using a specific phenolic compound, resveratrol, already showed that APP/PS1 mice, another AD mouse model, demonstrated a 2.2-fold increase in drebrin when fed resveratrol [71].…”

“…Anxiety was assessed with the dark-light emergence test as previously described [39,46,47]. Animals were positioned in the dark compartment and the time spent in the illuminated compartment was measured for 5 min.…”

“…Recognition memory was assessed as previously described with the novel object recognition (NOR) task, which is based on the spontaneous tendency of rodents to explore a novel object longer than a familiar one [39,45,46]. The NOR test was used to assess memory performance in this study because, compared to other tests like the Morris water maze or the Barnes maze, it is easier to perform and allows for a better distinction between cognitive and motivational domains, without depending on sensorimotor function and anxiety, which have been shown to be impaired in the 3xTg-AD mouse [39,45,46,48]. Moreover, this test has been successfully used with several other AD mouse models [49].…”

A novel recombinant 6Aβ15-THc-C chimeric vaccine (rCV02) mitigates Alzheimer’s disease-like pathology, cognitive decline and synaptic loss in aged 3 × Tg-AD mice

“…Some therapeutic strategies for AD attenuate synaptic dysfunction and improve cognitive behavior in AD models1718192021222324. Given the remarkable recovery of cognition in AD models of targeted-Aβ immunotherapy, it is necessary to determine the molecular correlations associated with improvement.…”