Glial cell dysregulation: a new perspective on Alzheimer disease

Abstract

Alzheimer disease (AD) is a major cause of dementia. Several mechanisms have been postulated to explain its pathogenesis, beta-amyloid (A beta toxicity, cholinergic dysfunction, Tau hyper-phosphorylation, oxidative damage, synaptic dysfunction and inflammation secondary to senile plaques, among others. Glial cells are the major producers of inflammatory mediators, and cytotoxic activation of glial cells is linked to several neurodegenerative diseases; however, whether inflammation is a consequence or the cause of neurodegeneration is still unclear. I propose that inflammation and cellular stress associated with aging are key events in the development of AD through the induction of glial dysfunction. Dysregulated inflammatory response can elicit glial cell activation by compounds which are normally poorly reactive. Inflammation can also be the major cause of defective handling of A beta and the amyloid precursor protein (APP). Here I review evidence that support the proposal that dysfunctional glia and the resulting neuroinflammation can explain many features of AD. Evidence supports the notion that damage caused by inflammation is not only a primary cause of neurodegeneration but also an inducer for the accumulation of A beta in AD. Dysfunctional glia can result in impaired neuronal function in AD, as well as in many progressive neurodegenerative disorders. We show that microglial cell activation is enhanced under pro-inflammatory conditions, indicating that glial cell responses to A beta related proteins can be critically dependent on the priming of glial cells by pro-inflammatory factors.

Inflammation, Aging, and Cancer: Tumoricidal Versus Tumorigenesis of Immunity

“…Exposure to foreign elements in natural immune-privileged tissues often results in sequestration of antigen and avoidance of tissue encounter with foreign elements, which limits activation of lymphoid tissues for humoral and/or cell-mediated (T cell) or delayed hypersensitivity responses by APCs such as brain microglial cells or DCs, that originate from myeloid precursors and invade the brain parenchyma before formation of brainblood barrier (BBB) and reside within CNS [86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102]. Due to low capacities of immune-privileged tissues for selfrenewal, activation of innate and adaptive immunity by infections or chronic irritations poses serious threats to these stress-sensitive tissues, and enhances cell death and risk of neurological or cellular disorders such as multiple sclerosis, demyelination of CNS, encephalomyelitis, stroke, Alzheimer's disease, retinitis, uveitis, ocular anterior chamber inflammatory complications, or testiculitis [4][5][6][7][8][9][10][11][12][13][86][87][88][89][90][91][92][93][94][95][96][97][98][99]…”

Neuroinflammation and microglia: considerations and approaches for neurotoxicity assessment

“…They comprise only 10% of the total cell population of the brain; yet, have multiple morphological and possible functional profiles as influenced by their environment [12,13]. The presence of activated glial cells localized to regions of brain injury was initially considered as a sign of pathology and, as such, considered for use as a sensitive marker to identify injury sites predestined for imminent tissue destruction [5]. However, we now know that microglia are in intimate contact with neurons, for which they serve important maintenance functions, are capable of responding to subtle changes in the microenvironment, and dynamically survey the CNS [14,15,16,17].…”

“…Such a threat can occur with disease, physical trauma, ischemia/hypoxia, or with cellular damage due to multiple initiating stimuli, including exposure to neurotoxicants. For additional reading on the issue of heterogeneity of microglia responses the reader is directed to the following references [1,2,3,4,5].…”

Parp and Cell Death or Protection in Rat Primary Astroglial Cell Cultures Under LPS/IFNγ Induced Proinflammatory Conditions

“…The involvement and relevance of glial cells in neurodegenerative diseases is widely recognized [45,46]. To induce a well established proinflammatory pathway characterized by iNOS induction, primary rat astroglial cell cultures were treated with LPS and IFNc, at different concentrations ranging between 1 and 4 lg/ml and 100-400 U/ml, respectively, for 18 h, time that we previously found to be necessary to obtain a marked iNOS expression [47].…”