The Classification of Microglial Activation Phenotypes on Neurodegeneration and Regeneration in Alzheimer’s Disease Brain

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive decline of cognitive function and memory formation. There is no therapeutic that can halt or reverse its progression. Contemporary research suggests that age-dependent neuroinflammatory changes may play a significant role in the decreased neurogenesis and cognitive impairments in AD. The innate immune response is characterized by pro-inflammatory (M1) activation of macrophages and subsequent production of specific cytokines, chemokines, and reactive intermediates, followed by resolution and alternative activation for anti-inflammatory signaling (M2a) and wound healing (M2c). We propose that microglial activation phenotypes are analogous to those of macrophages and that their activation plays a significant role in regulating neurogenesis in the brain. Microglia undergo a switch from an M2- to an M1-skewed activation phenotype during aging. This review will assess the neuroimmunological studies that led to characterization of the different microglial activation states using AD mouse models. It will also discuss the roles of microglial activation on neurogenesis in AD and propose anti-inflammatory molecules as exciting therapeutic targets for research. Molecules like interleukin-4 and CD200 have proven to be important anti-inflammatory molecules in the regulation of neuroinflammation in the brain, and they will be discussed in detail for their therapeutic potential.

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…The inflammation can be acute or chronic. The inflammatory reaction that involves in most neurodegenerative diseases (Craft et al 2006;Liu et al 2013;Pizza et al 2011;Sudduth et al 2013;Varnum and Ikezu 2012), is often termed ''neuroinflammation''. Microglia, which is supposed to be the resident macrophages of the brain, and atrocities are the main cells that involve in this process.…”

“…Microglia, which is supposed to be the resident macrophages of the brain, and atrocities are the main cells that involve in this process. In the brains of both AD individuals and transgenic animal models, it was found that Ab plaques are surrounded by activated glial cells (Bauer et al 1991;Cagnin et al 2001;Fillit et al 1991;Liu et al 2013;Varnum and Ikezu 2012). Activated microglia and astrocytes strongly secrete inflammatory components such as pro-inflammatory cytokines, chemokines, complement, macrophage inflammatory proteins, monocyte chemoattractant proteins, reactive oxygen species (ROS), nitric oxide (NO) prostaglandins, leukotrienes, thromboxanes and so on (Akiyama et al 2000;Griffin et al 1998;Mrak et al 1995;Town et al 2005;Tuppo and Arias 2005).…”

“…Activated microglia and astrocytes strongly secrete inflammatory components such as pro-inflammatory cytokines, chemokines, complement, macrophage inflammatory proteins, monocyte chemoattractant proteins, reactive oxygen species (ROS), nitric oxide (NO) prostaglandins, leukotrienes, thromboxanes and so on (Akiyama et al 2000;Griffin et al 1998;Mrak et al 1995;Town et al 2005;Tuppo and Arias 2005). The released inflammatory molecules, especially some cytokines such as interleukin (IL)-18, IL-1b and tumor necrosis factor (TNF)-a, impair the balance of normal neurophysiologic condition that correlates with cognition and learning and memory (Fillit et al 1991;Gemma and Bickford 2007;Jankowsky and Patterson 1999;Liu et al 2013;Varnum and Ikezu 2012). These secreted inflammatory mediators, in turn, activate more microglia and astrocytes to produce inflammatory molecules.…”

Neurodegenerative diseases and therapeutic strategies using iron chelators

“…However, there are certain observations which do not concur with this hypothesis. Firstly the removal of Aβ from the brains of animal models and humans does not halt the progression of the disease and secondly Aβ is often present in healthy brains [40].…”

“…There is an increase in the number of 'activated' microglia cells (of unknown phenotype) surrounding senile plaques in the cerebral cortex, Aβ deposits are present in T cell, and there is a significant decrease in CD200 protein and mRNA in AD hippocampus and inferior temporal gyrus, but not cerebellum. [40]. Therefore a second hypothesis has been presented indicating that neuronal damage that occurs in AD is not entirely due to Aβ deposition or intracellular tau accumulation but caused by an abnormal immune response.…”