Effects of human intravenous immunoglobulin on amyloid pathology and neuroinflammation in a mouse model of Alzheimer’s disease

Abstract

BackgroundHuman intravenous immunoglobulin (hIVIG) preparation is indicated for treating primary immunodeficiency disorders associated with impaired humoral immunity. hIVIG is known for its anti-inflammatory properties and a decent safety profile. Therefore, by virtue of its constituent natural anti-amyloid beta antibodies and anti-inflammatory effects, hIVIG is deemed to mediate beneficial effects to patients of Alzheimer’s disease (AD). Here, we set out to explore the effects of hIVIG in a mouse model of AD.MethodsWe treated APP/PS1dE9 transgenic and wild-type mice with weekly injections of a high hIVIG dose (1 g/kg) or saline for 3 or 8 months. Treatment effect on brain amyloid pathology and microglial reactivity was assessed by ELISA, immunohistochemistry, RT-PCR, and confocal microscopy.ResultsWe found no evidence for reduction in Aβ pathology; instead 8 months of hIVIG treatment significantly increased soluble levels of Aβ40 and Aβ42. In addition, we noticed a significant reduction in CD45 and elevation of Iba-1 markers in specific sub-populations of microglial cells. Long-term hIVIG treatment also resulted in significant suppression of TNF-α and increase in doublecortin positive adult-born neurons in the dentate gyrus.ConclusionsOur data indicate limited ability of hIVIG to impact amyloid burden but shows changes in microglia, pro-inflammatory gene expression, and neurogenic effects. Immunomodulation by hIVIG may account for its beneficial effect in AD patients.

Association of CD33 polymorphism rs3865444 with Alzheimer's disease pathology and CD33 expression in human cerebral cortex

“…This might suggest that there are greater numbers of microglia in A/A cases, though this would not agree with a previous finding (Bradshaw et al, 2013); alternatively the microglia in the A/A cases might be more activated as a result of reduced CD33 anti-inflammatory activity. IBA-1 (ionized calcium binding adapter protein-1) is a widely used marker to assess microglial abundance, though its expression can also be upregulated with microglial activation (Koppel et al, 2014;Puli et al, 2012;Zotova et al, 2013). Reduced amounts of CD33 protein was a feature of peripheral blood monocytes from A/A subjects (Bradshaw et al, 2013).…”

A phase 3 trial of IV immunoglobulin for Alzheimer disease

“…7 Administration of IVIg in murine models of AD resulted in minimal plaque clearance without microhemorrhage or vasogenic edema and promoted neurogenesis. 8 Prior human studies involved small numbers of participants but showed good safety and tolerability, though were underpowered to detect efficacy. [9][10][11][12][13][14] We report the results of a phase 3 trial testing the safety and efficacy of 2 doses of IVIg in mild to moderate AD dementia.…”

Cerebral dopamine neurotrophic factor improves long-term memory in APP/PS1 transgenic mice modeling Alzheimer's disease as well as in wild-type mice

“…However, a confound in the interpretation is that at the age of 13−14 months, when the mice were euthanized the proliferation rate was already very low also in the WT mice, leaving little space for an anti-apoptotic factor to substantially increase the number. At least, we can exclude the possibility of that CDNF had increased proliferation of neuronal stem cells, an effect that we have previously demonstrated in the same mice treated with human polyclonal immunoglobulin [30].…”

“…These models also differ greatly in that acute administration of either 6-OHDA or MPTP induces acute neuronal death, whereas no notable neuron loss has been reported in the transgenic amyloid plaque producing mice [29]. Instead, the pathology is characterized by gradual increase in the number of amyloid plaques surrounded by chronic neuroinflammation [30] and abnormalities in synaptic microstructure [29]. We found no effect of CDNF treatment on amyloid pathology, which is in line with our earlier observations of no change in brain amyloid load after manipulation of functional TrkB-receptor levels [27] or partial BDNF gene knockout [28], as well as with a recent study reporting lack of effect on amyloid levels by GDNF gene therapy in APP/PS1/tau transgenic mice [9].…”