Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) affects more than 18 million people worldwide and is characterized by progressive memory deficits, cognitive impairment and personality changes. The main cause of AD is generally attributed to the increased production and accumulation of amyloid-beta (Abeta), in association with neurofibrillary tangle (NFT) formation. Increased levels of pro-inflammatory factors such as cytokines and chemokines, and the activation of the complement cascade occurs in the brains of AD patients and contributes to the local inflammatory response triggered by senile plaque. The existence of an inflammatory component in AD is now well known on the basis of epidemiological findings showing a reduced prevalence of the disease upon long-term medication with anti-inflammatory drugs, and evidence from studies of clinical materials that shows an accumulation of activated glial cells, particularly microglia and astrocytes, in the same areas as amyloid plaques. Glial cells maintain brain plasticity and protect the brain for functional recovery from injuries. Dysfunction of glial cells may promote neurodegeneration and, eventually, the retraction of neuronal synapses, which leads to cognitive deficits. The focus of this review is on glial cells and their diversity properties in AD.

1

Activation of the glial cell response toward the formation of senile plaque in Alzheimer's disease. The overproduction and extracellular deposition of amyloid β-peptide (AβP) and an intracellular deposition of neurofibrillary tangles (NFT) initiates the pathogenesis of Alzheimer's disease (AD). The production of complement components (C1q, C3 and C5) is the first stage in response to Aβ deposition, resulting in the attraction and activation of microglial cells. Both microglial cells and astrocytes produce multiple pro-inflammatory and neurotoxic factors: transforming growth factor (TGF)-1; tumour necrosis factor (TNF)-α; interleukin-1 (IL-1); CC-chemokine ligand (CCL); antichymotrypsin (ACT); reactive oxygen species (ROS) and cyclooxygenase 2 (COX2). Activated microglial cells express various scavenger receptors (SRs) that mediate phagocytosis of Aβ, such as CD36, SR-A. Microglial cells can also degrade Aβ by releasing Aβ-degrading enzymes, such as insulin-degrading enzyme (IDE).

2

Glia–endothelia cell interaction in AD pathogenesis. Mediators released by astrocytes activate neighbouring cells and amplify the local, initial innate immune response further, modify BBB permeability and attract immune cells from the blood circulation into the neural tissue, thus supporting an adaptive immune response. Activated microglia up-regulate: MHC class II molecules, CD14, Toll-like receptors (TLRs) and CD40; and produce cytokines: transforming growth factor-β (TGF-β); tumour necrosis factor-α (TNF-α); interleukins and chemokines. TGF-β1 potentiates Aβ production in human astrocytes and thus favouring continuing deposition of Aβ, which in turn activates glial cell synthesis and the release of a number of cytokines. Low-density lipoprotein (LDL) receptor-related protein (LRP-1) and receptor for advanced glycation end products (RAGE) perform opposite functions in transporting Aβ. The weakening of the vessel wall is the likely cause of intracerebral haemorrhage.