MICROGLIA CELLS ROS PRODUCTION BY BETA-AMYLOID STIMULATION OF NADPH OXIDASE IS SUBSTAINED BY CHLORIDE INTRACELLULAR CHANNEL 1(CLIC1)PERMEABILITY.

Alzheimer’s disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain. Genetic, biochemical, and behavioral research suggest that physiologic generation of the neurotoxic Aβ peptide from sequential amyloid precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and highly complex fashion by a series of sequential proteases. Aβaccumulates in the brains of elderly individuals due to changes in APP metabolism or Aβ elimination. Particularly, AD brain is characterized by plaques containing beta-amyloid protein surrounded by astrocytes and reactive microglia. Activation of microglia by beta-amyloid initiates production of reactive oxygen species (ROS) by the plasmalemmal NADPH oxidase. The resultant oxidative stress contributes to neurodegeneration in AD. In previous study has been reported from our laboratory and from others that betaamyloid upregulates a chloride current mediated by the chloride intracellular channel 1 (CLIC1) protein in microglia. In the present study we show that CLIC1 is responsible of maintaining the resting membrane potential of microglia cells more hyperpolarized during acute beta-amyloid stimulation. This condition is functional to a more efficient ROS production. It is important to highlight that the specific role of microglia cells is to attach and destroy external bran intruders such as bacteria. In this case the action of the immune competent cells is localized in the infection site. Even if all the toxic products released by the activated microglia are armful for neurons as well, the damaged area results insignificant for the central nervous system in its extend. However, in the case of an over production of aberrant proteins like beta-amyloid, microglia cells recognize the aggregation of misfolded protein as a threat and try to destroy them. Unfortunately beta-amyloid oligomers are present in vast areas of the brain and in particular in the hippocampus region and in the cortex. Thus ROS overproduction become armful for a large amount of neurons resulting in cognitive impairment and eventually in massive neuronal death. Since the synergy between CLIC1 and NADPH ROS production, the chloride channel could represent a valid target to counteract the neurodegenerative process. The aim of the present work is to uncover the molecular mechanism that link CLIC1 to ROS production by showing the importance of CLIC1 chloride current to antagonize the loss of negative charges due to the work of membrane NADPH oxidase.