β-Secretase activity in rat astrocytes: translational block of BACE1 and modulation of BACE2 expression

Abstract

BACE1 and BACE2 are two closely related membrane-bound aspartic proteases. BACE1 is widely recognized as the neuronal β-secretase that cleaves the amyloid-β precursor protein, thus allowing the production of amyloid-β, i.e. the peptide that has been proposed to trigger the neurodegenerative process in Alzheimer's disease. BACE2 has ubiquitous expression and its physiological and pathological role is still unclear. In light of a possible role of glial cells in the accumulation of amyloid-β in brain, we have investigated the expression of these two enzymes in primary cultures of astrocytes. We show that astrocytes possess β-secretase activity and produce amyloid-β because of the activity of BACE2, but not BACE1, the expression of which is blocked at the translational level. Finally, our data demonstrate that changes in the astrocytic phenotype during neuroinflammation can produce both a negative as well as a positive modulation of β-secretase activity, also depending on the differential responsivity of the brain regions.

Ceruloplasmin Oxidation, a Feature of Parkinson's Disease CSF, Inhibits Ferroxidase Activity and Promotes Cellular Iron Retention

“…Primary rat hippocampal neurons (ϳ80% purity) or pure astrocytes were prepared from 2-to 3-d-old Sprague Dawley rats, in respective accordance with Codazzi et al (2006) and Bettegazzi et al (2011). The Institutional Animal Care and Use Committee of the San Raffaele Scientific Institute approved the experimental procedures.…”

Astrocyte signaling and neurodegeneration

“…In keeping, recent studies in vitro confirmed that, under normal conditions, astrocytes possess the APP-processing machinery for generating Aβ peptide, i.e., APP itself, BACE1 and/or its close homolog BACE2. 76,80,81 Furthermore, Aβ peptide was described to transcriptionally regulate the expression of the astrocytic BACE1 via the calcineurin/nuclear factor of activated T cells 4 (NFAT4) or nuclear factor-κB (NF-κB) signaling pathways, 82,83 suggesting a feed-forward mechanism to maintain or amplify Aβ deposits in astrocytes. More controversial is the issue of reactive astroglia as some studies indicated that cultured astrocytes, activated with cytokine combinations, positively regulate β-secretase activity and Aβ secretion, 84 whereas others found opposite results.…”

“…More controversial is the issue of reactive astroglia as some studies indicated that cultured astrocytes, activated with cytokine combinations, positively regulate β-secretase activity and Aβ secretion, 84 whereas others found opposite results. 76 A correlation between the deposition of Aβ protein in the extracellular space of forebrain regions and the progressive decline in cognitive functions was originally established in morphological and biochemical studies in AD patients. [85][86][87] Subsequent results obtained in various transgenic AD models provided additional evidence that cognitive deficits are the consequence of the synaptic failure induced by Aβ.…”

“…72 The β-site APP-cleaving enzyme 1 (BACE1) has been identified as the β-secretase that iniziates the production of Aβ peptide. 73 Since neurons express higher levels of BACE1 than astrocytes, [74][75][76] it was initially proposed that they are the major source of Aβ in brain. 74 However, in both autoptic AD cases and transgenic mice, BACE1 expression and Aβ deposits are not only restricted to neurons, but they co-localize also with astroglial markers.…”

The Normal and Pathologic Roles of the Alzheimer's β-secretase, BACE1

“…The physiological and pathological role of BACE2 remains unclear. BACE2 is expressed in glial cells and may contribute to Aβ generation within this cell type although the mechanism requires elucidation [35, 45]. Glial cells play a role in AD amyloidogenesis, and early evidence for a role for BACE2 in glial amyloidogenic processing in Down syndrome patients suggests further investigation.…”