The role of astrocytes in amyloid β-protein toxicity and clearance

The deposition of the amyloid beta-protein (A beta) in the brain is a pathological hallmark of Alzheimer's disease (AD). Here, A beta deposits occur as A beta plagues in the brain parenchyma and in the walls of cerebral and leptomenigeal blood vessels. Astrocytes are considered to be involved in the clearance of A beta from the brain parenchyma into the perivascular space, across the blood-brain barrier, or by enzymatic degradation. As such it has been assumed that clearance of A beta by astrocytes is beneficial. In a recent study published in Experimental Neurology Mulder et al. (2012; 233: 373-379) report changes in neprilysin and scavenger receptor class B member 1 gene expression in astrocytes exposed to fibrillar A beta depending on the availability of amyloid-associated proteins, especially apolipoprotein E (apoE). Astrocytes from AD patients did not show this response in gene expression. Reactive astrocytes and A beta containing astrocytes are common findings in the AD brain. A loss of excitatory amino acid transporter 2 expression in perivascular astrocytes of APOE epsilon 4-positive AD cases and an alteration of neuronal apoE metabolism in the event of perivascular drainage of apoE-A beta complexes has also been described. As such, reactive and compensatory changes in AD astrocytes compete with supporting functions of astrocytes finally leading to an impairment of metabolic support and transmitter recycling in the brain. In summary, exposure of astrocytes to increased amounts of A beta over a long period in time very likely impairs the above mentioned supporting functions of astrocytes in AD patients because these cells have to clear large amounts of A beta and, thereby, neglect their other functions. (C) 2012 Elsevier Inc. All rights reserved.