Background: Alzheimer’s disease (AD) is associated with age-associated central nervous
system degeneration and dementia. This decline in the function correlates with deposition of Aβ peptide
containing plaques and associated reactive gliosis. The inflammatory phenotype of microglia, in particular,
is often considered detrimental to cognitive function in AD. In addition to the changes in the CNS,
altered immune changes in the periphery have recently been observed in AD suggesting a critical immune-
related communication between the periphery and the brain.
Objective: We hypothesized that modulating the peripheral immune system may alter the proinflammatory
gliosis associated with AD. Therapeutic antibodies against the α4β1 integrin receptor have been
used clinically to attenuate the ability of various immune cells to adhere to endothelium and migrate into
target tissues such as the intestines (Crohn’s disease) or brain (multiple sclerosis). We hypothesized that
a similar peripheral antibody-based therapy would attenuate gliosis by altering immune cell infiltration
or phenotype in peripheral organs and the brain using an APP/PS1 mouse model of Alzheimer’s disease.
Method: Littermate control wild-type and APP/PS1 mice were tail vein injected with either saline, isotype
control (IgG2b), or an antibody recognizing α4-integrin, anti-CD49d, once a week for 4 consecutive
weeks. To understand CNS and peripheral immune changes, brains and spleen were used.
Results/Conclusion: Our data suggests that the antibody therapy was able to reduce microgliosis, astrogliosis,
and synaptic changes in the APP/PS1 mice compared to isotype control injections without
changing amyloid-β plaque load. Interestingly, both isotype control and antibody therapy also reduced
the number of proinflammatory cytokines in the spleen although changes in the brain were less robust.
The anti-CD49d and isotype control treatments also reduced CD4 immunoreactivity in the brains, suggesting
a possible mechanism for attenuation of inflammation in the brain. This data suggests that it is
indeed feasible to alter the immune component of AD brain changes using a clinically feasible strategy
of delivering a particular subtype of IgG or epitope selective antibodies that target infiltration of the
peripheral immune system.