Ameliorating Alzheimer’s Disease tau pathology through immunomodulation: A novel application for glatiramer acetate

Identification: Dionisio-Santos, Dawling


Description

Ameliorating Alzheimer's Disease tau pathology through immunomodulation: A novel application for glatiramer acetate
 
Dawling A. Dionisio-Santos, John A. Olschowka, M. Kerry O'Banion
University of Rochester Medical Center, Department of Neuroscience
      
Chronic neuroinflammation has long been thought to be involved in the pathophysiology of Alzheimer's Disease (AD). Neuroinflammation can be regulated by alterations in the peripheral immune system.  Previous research has shown that upregulation of proinflammatory cytokines in the periphery leads to CNS inflammation and a decrease in amyloid  plaque clearance. In addition, work from our lab has shown that overexpression of IL-1 in the CNS leads to an increase in hyperphosphorylated tau, the precursor of neurofibrillary tangles. We hypothesize that an anti-inflammatory immunomodulatory agent might have beneficial effects. One candidate is the multiple sclerosis drug Glatiramer acetate (GA), which is thought to act by biasing type 2 helper T (Th2) cell responses. Among the effector cytokines of Th2 cells are IL-4 and IL-10, which are known to participate in the suppression of pathological inflammation. Treatment with GA causes a decrease in plaque load in amyloidogenic models, however its effect on tau hyperphosphorylation has not been described. We administered weekly subcutaneous injections of GA or PBS to 15 month-old 3xTg AD mice, which develop both amyloid and tau pathology, for a period of one month. After the last injection, mouse cognitive performance was assessed utilizing novel object recognition (NOR) and the Lashley III maze (LIII). Following behavioral tasks, brains were collected, and amyloid and tau pathology were measured utilizing immunohistochemistry, western blot and ELISA. Our results indicate that GA positively modulated behavioral performance in both tasks. GA did not lead to a reduction of amyloid pathology in this model. In contrast, tau phosphorylation was decreased in GA treated animals. This effect on tau pathology was accompanied by a decrease in the activated isoforms of tau kinases. In conclusion, our results indicate that peripheral anti-inflammatory immunomodulation can influence regulation of tau phosphorylation. Furthermore, we provide additional evidence for the use of GA as a therapeutic agent for AD.
 
Supported by NIH R01 AG030149.
 

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