Study Shows Not All IVIG Products Are Created Equal in Alzheimer Disease

A recent study found that 1 specific intravenous immunoglobulin (IVIG) product was more effective than others in counteracting the cognitive deficits, ameliorating b-amyloid (Ab) deposits, and tau phosphorylation among mice with Alzheimer disease (AD).

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Although the etiology of AD is not fully understood, experts believe that the most important pathophysiological characteristics are extracellular Ab deposition that form senile plaques, as well as the formulation of neurofibrillary tangles caused by intracellular hyperphosphorylated tau (p-tau) protein. A growing body of research also shows that AD development is significantly impacted by inflammation.

Because of this growing research, investigators have begun evaluating the use of IVIG in AD. IVIG contains the full spectrum of human antibodies and is known to inhibit inflammation. It has been used to treat patients with autoimmune diseases for nearly 40 years and has a well-established safety and efficacy profile in this patient population. In 2002, researchers showed that IVIG contains anti-Ab antibodies and since then, a variety of AD-relevant antibodies were found in IVIG, including anti-tau antibodies and anti-advanced glycation end-product receptor antibodies.

Despite these findings, clinical trials with IVIG for AD have shown inconsistent effects. At least 5 randomized controlled trials of IVIG for patients with AD have been conducted globally since 2013, but they have had varying results. The underlying mechanism is still not understood, and the investigators noted that the impact of IVIG on the results of clinical trials for AD has not been studied enough.

In their new study, investigators examined the neuroprotective effects of IVIG from 3 different manufacturers in triple-transgenic (3xTg-AD) mice. Behavioral tests, enzyme-linked immunosorbent assay (ELISA), Luminex, immunohistochemistry (IHC), proteomics, and parallel reaction monitoring (PRM) were used to determine whether the 3 IVIG had different efficacy on AD. Additionally, part of the potential mechanisms of action were revealed.

The 3 kinds of IVIG were numbered IVIG-A, IVIG-B, and IVIG-C and were produced by different manufacturers in China. Their preparation processes are not identical and, notably, the plasma donors have great differences in race, ethnicity, geography, and diet.

Three mice from each IVIG group were examined and the whole brain was taken to detect human IgG (hIgG). Interestingly, the hIgG concentrations in IVIG-C and IVIG-A were significantly higher than the concentrations in IVIG-B. After intraperitoneal injection of IVIG into the mice, the bioavailability of the 3 IVIG products was different.

The 3 products also improved cognitive decline in 3xTg-AD mice to different degrees. After the IVIG injection and another 3 months of normal feeding, all mice were tested for cognitive behavior. When placed in a new environment, the 3xTg-AD mice traveled a less total distance compared with the control group, and the 3xTg-AD mice spent less time exploring a novel object used to evaluate recognition memory. Based on these findings, the investigators concluded that IVIG-C improved cognitive and motor decline in 3 behavioral outcomes, while IVIG-A and IVIG-B only improved the motor and autonomous decline in an open-field experiment test.

The degree to which the 3 IVIG products ameliorated pathological alterations in the 3xTg-AD mice also varied. IHC testing showed that the area of hippocampal Ab-positive plaques in the control group was significantly larger than that in the wild-type group. Additionally, the deposition of Ab was alleviated in the hippocampus of 3xTg-AD mice by IVIG-C, rather than by IVIG-A or -B. The number of p-tau was also reduced by IVIG-C rather than IVIG-A or -B.

Finally, IVIG-A and IVIG-C significantly suppressed the secretion of pro-inflammatory factors produced by activated glial cells better than IVIG-B. IVIG-C also had a significant impact on antigen processing and presentation by major histocompatibility complex (MHC) class 1 molecules, whereas IVIG-A had a significant effect on hematopoietic or lymphoid organ development and IVIG-B affected response to bacterium process.

Based on these findings, the investigators concluded that IVIG-C was the only product to show overall improvement in neuroprotection, including alleviating cognitive decline, ameliorating Ab deposition and tau phosphorylation, attenuating microglia and astrocyte activation, and inhibiting the secretion and expression of pro-inflammatory factors. The results do importantly suggest that IVIG has promising therapeutic effects in AD treatment, although further research is necessary to understand the molecular mechanism of IVIG-C against AD.

Reference

Fei Z, Ban B, Pei R, et al. Neuroprotective Effects of IVIG against Alzheimer Disease via Regulation of Antigen Processing and Presentation by MHC Class I Molecules in 3xTg-AD Mice. J Prev Alzheimers Dis. 2023;10:581-594. doi:10.14283/jpad.2023.56