Title:Intravenous Immunoglobulins for Alzheimer's Disease
Volume: 11
Issue: 7
Author(s): Lakshman Puli, Heikki Tanila and Norman Relkin
Affiliation:
Keywords:
Alzheimer's disease, amyloid beta, antibodies, human intravenous immunoglobulins, IgG sialylation, immunomodulation,
microglia, neurogenesis, neuroinflammation, oligomers.
Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disease associated with intracerebral accumulation of
aggregated amyloid-beta (Aβ) and tau proteins, as well as neuroinflammation. Human intravenous immunoglobulin
(IVIG) is a mixture of polyclonal IgG antibodies isolated and pooled from thousands of healthy human donors. The scientific
rationale for testing IVIG as a potential AD treatment include its natural anti-Aβ antibody activity, its favorable
safety profile and inherent anti-inflammatory/immunomodulatory properties. Over the past decade, several clinical and
pre-clinical experimental findings, advanced our knowledge about biological and therapeutic properties of IVIG that are
relevant to AD therapy. Anti-amyloid antibodies in IVIG show significantly higher binding avidity for amyloid oligomers
and fibrils than for Aβ monomers. In a double transgenic murine model of AD, intracerebral injection of IVIG causes
suppression of Aβ fibril pathology whereas long term peripheral IVIG treatments causes elevation of total brain Aβ levels
with no measurable impact on Aβ deposits or tendency for inducing cerebral microhemmorhage. Furthermore, chronic
IVIG treatment suppressed neuroinflammation and fostered adult hippocampal neurogenesis. In clinical studies with AD
patients, IVIG showed an acceptable safety profile and has not been reported to increase the incidence of amyloid related
imaging abnormalities. Preliminary studies on small number of patients reported clinical benefits in mild to moderate
stage AD patients. However, double blind, placebo controlled studies later did not replicate those initial findings. Interestingly
though, in APOE4 carriers and in moderate disease stage subgroups, positive cognitive signals were reported. Nevertheless,
both clinical and experimental (mouse) studies show that antibodies in IVIG can accumulate in CNS and its biological
activities include neutralization of Aβ oligomers, suppression of neuroinflammation and immunomodulation. Identifying
mediators of IVIG’s effects at the cellular and molecular level is warranted. In light of its favourable safety profile
and aforementioned biological properties, IVIG is still an enigmatic experimental candidate with enormous potential for
being an AD therapeutic.
