Anti-α4β1 Integrin Antibodies Attenuated Brain Inflammatory Changes in a Mouse Model of Alzheimer’s Disease

Abstract

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.

Blockade of α4 integrins reduces leukocyte–endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer’s disease

“…Prolonged microglial activation may have a detrimental role in AD, and here we show that the blockade of α4 integrin inhibits this process in 3xTg-AD mice, highlighting the anti-inflammatory effect of anti-adhesion therapy. Our results agree with recent neuropathology studies in APP/PS1 mice, a model of brain amyloidosis, showing that treatment with an anti-CD49d antibody reduces microgliosis, astrogliosis, CD4 immunoreactivity and synaptic changes, without altering the Aβ plaque load 46 . However, we observed lower levels of intracellular Aβ accumulation during earlier stages of AD and determined how blocking α4 integrins affects cognitive functions using a more complex model, in which mice develop both amyloid and tau pathologies, thus more closely representing AD neuropathology in humans.…”

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…In the mouse EAE model, NZ treatment resulted in more NF-positive cells, indicating reduced axonal damage [285]. Interestingly, NZ normalized the synaptic changes found in the mouse APP/PS1 model of AD by increasing the PSD-95 levels [284]. Moreover, RRMS patients treated with NZ showed an increase in the concentrations of NAA, Cr, pCr and glutamate in lesioned white matter [185].…”

“…Overall, most studies point to an effect of NZ on the attenuation of microgliosis by reducing the activated M1 microglia response in various disease models, such as in the APP1/PS1 mouse model of AD [284] and in EAE mice [285]. The NZ treatment of MS patients also reduced the pro-inflammatory microglia phenotype, as established by PET scanning, using the pro-inflammatory microglia marker 11C-PK11195, which binds to the mitochondrial outer-membrane translocator protein TSPO [286,287].…”

“…Astrogliosis was reduced in a mouse AD model treated with NZ, when compared to untreated animals and based on the number of reactive A1 GFAP-positive astrocytes and the protein expression level of GFAP [284]. Moreover, following the NZ treatment of EAE mice, the protein levels of the inflammation-associated protein lipocalin 2 (LCN2) [293,294] was reduced in inflammation-activated GFAP-positive astrocytes [295].…”

Anti-integrins

“…The a4 integrin-dependent leukocyte trafficking promotes cognitive impairment in multiple sclerosis (MS), Alzheimer's disease (AD), and other neuropathological disorders, which suggests that blocking a4 integrins might offer a new therapeutic strategy in MS, AD, and other neuronal diseases. The FDA-approved humanized monoclonal antibody against the cell adhesion molecule a4integrin, namely natalizumab, is indicated for the improvement of disability and reduction of relapse rate in MS patients (Mazdeh et al 2018;Engelhardt and Kappos 2008;Li et al 2018;Manocha et al 2018;Dattoli et al 2018;Pietronigro et al 2019).…”