Astrocytes in Alzheimer's Disease
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The blood-brain barrier (BBB) is essential for the normal function of the central nervous system since it restricts influx of most compounds from blood to brain. During several neurologic conditions the integrity of the BBB is impaired and progressively loses its function resulting in BBB breakdown and damage to neurons and other brain cells, such as during Alzheimer’s disease (AD). Astrocytes play a major part in the formation and maintenance of the BBB and are implicated in the progression of Alzheimer’s disease. In AD, the β-amyloid peptide (Aβ) accumulates in plaques which results in initiation of a cascade of events leading to neurodegeneration and dementia. This peptide activates astrocytes which are found to surround Aβ plaques and to intracellularly contain Aβ. Several data indicate that astrocytes in close proximity to Aβ plaques are capable to intracellularly accumulate substantial amounts of Aβ. Aβ-overburdened astrocytes have been shown to produce astrocyte-derived plaques. In contrast, the amyloid precursor protein and the β-site APP-cleaving enzyme have been localized in activated astrocytes which are able to produce Aβ. Thus, it remains elucidated whether activated astrocytes produce Aβ or whether they phagocytose and degenerate Aβ. Astrocytes are also implicated in chronic inflammation in AD. They have been found to produce pro- and anti-inflammatory factors and facilitate complex interactions with several inflammatory cells. Astrocytes express several Aβ receptors which are responsible for Aβ phagocytosis, mainly the low-density lipoprotein receptor (LDLR) and the LDLR-related receptor (LRP-1). ApoE is implicated in the clearance of Aβ by forming an ApoE-Aβ complex and binding the LRP-1 receptor on astrocytes. The frequency of certain isoforms of ApoE in late-onset familial AD patients is almost four times higher than in the general population. In addition, mechanisms which as well add to the progression of AD are the aquaporin channels which facilitate the osmotic driven bidirectional water transport across cell membranes. Several studies suggest there is a possible association of astrocyte APQ1 with Aβ deposition in AD brains. The prostaglandin transporter mediates the secretion of several pro-inflammatory molecules which were postulated to be upregulated in patients with AD. However, the levels of the prostaglandin transporter is found to be decreased in astrocytes in AD patients. In patients with AD, inefficient clearance of Aβ seems to be the fundamental event leading to accumulation of Aβ in the brain. To clear Aβ from the brain and prevent neurotoxicity, Aβ has to be transported across the BBB. Accumulation of Aβ in the vessel walls is the primary pathogenic event in AD and results in disruption of the BBB. The methods by which astrocytes are implicated in AD remain to be elucidated. However, the altered activity of astrocytes seem to play an important role in the disruption of the BBB in AD patients.