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Alzheimer's Disease Research
Completed Award

Dr. Pritam Das

Pritam Das, Ph.D.

Mayo Clinic Jacksonville
Jacksonville, FL

Title: Cytokine Modulation Of Amyloid Beta Associated Pathologies In APP Mouse Models Of Alzheimer's Disease
Non-Technical Title: Effect Of Inflammation In The Brain On Disease Progression In Alzheimer's Disease

Duration: April 1, 2009 - July 31, 2012
Award Type: Standard
Award Amount: $399,999

Summary:

The experiments proposed here will establish an experimental template to study potential disease modifiers, their roles in modulating Alzheimer's disease (AD) like pathologies and their use in the future design of potential AD therapeutics.

Details:

Alzheimer's disease (AD) and other related dementia are accompanied by changes in inflammatory markers (cytokines) in the brain. This study will observe how over-expression of specific cytokines affects amyloid beta deposition in an AD mouse model. We hypothesize that immune modulating mediators, like cytokines, play both protective and harmful roles and will help us investigate their role in promoting or reducing amyloid beta associated pathologies in AD. In addition to gaining insight into the cytokines' roles in altering the pathology, these studies may provide the rationale for development of novel therapeutic approaches for the treatment of AD.

Publications:

P.Chakrabarty et al., Massive gliosis Induced by Interleukin-6 suppresses A deposition in vivo: Evidence against inflammation as a driving force for amyloid deposition. FASEB J.(2010) Feb;24(2): pp. 548-59 PubMed Icon Google Scholar Icon

(This study resulted in an unexpected finding that when the brain's immune cells (microglia) are activated by the Interleukin-6 protein (IL-6), they actually prevented the formation of amyloid plaques-considered a hallmark of AD pathology, instead of causing them to form more amyloid plaques or making the disease worse. This article was featured in a press release http://www.medicalnewstoday.com/articles/167661.php)

Chakrabarty et al., Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Mol Neurodegener. 2012 Jul 29;7:36. PubMed Icon Google Scholar Icon

Progress Updates:

Over many years, a protein called amyloid beta forms sticky "plaques" in the brains of people with Alzheimer's disease (AD), ultimately killing the surrounding neurons and causing memory loss and other cognitive problems. Inflammation or excessive action of the brain's immune cells (called microglia) is another hallmark of the disease. Researchers generally have assumed that inflammation equates with injury and toxicity to neurons, but the relationship between microglia and amyloid plaques remains unclear. To investigate whether a higher degree of brain inflammation would increase the amount of plaques, we used mice that carry AD-causing genetic mutations and produce amyloid plaques in the mouse brain. We then introduced a modified virus to over-produce proteins called cytokines, namely Interleukin-6 (IL-6) and Interferon gamma (IFN-gamma). Both of these cytokines are known to be highly inflammatory, and are prevalent in the brains of patients with AD.

In all experiments examined to date, these cytokines induced robust inflammation and activation of microglia in the brains of mice (IFN-gamma expression in the brain but not IL-6 also caused some neuronal damage). Unexpectedly, expression of both inflammatory cytokines in the brain significantly decreased the amount of amyloid plaques. This is perhaps due to the activation of the microglial cells' phagocytosis function (the ability to engulf and ingest bacteria or other foreign bodies) and activation of other components of the brain's immune system (e.g. complement system proteins), helping to prevent and/or remove amyloid-beta deposits from the brain. These exciting results suggest that these inflammatory cytokines may play an important role in restricting amyloid plaque deposition and growth early in the disease process and thus, manipulating and activating the brain's own microglial cells may hold promise for the future development of therapies for AD.