Multiple cellular and molecular mechanisms Are involved in human Aβ clearance by transplanted adult astrocytes

Abstract

Astrocytes and microglia are able to degrade potentially neurotoxic β-amyloid (Aβ) deposits typical for Alzheimer's disease (AD) pathology. Contrary to microglia, astrocytes degrade human Aβ from tissue sections in vitro without any additional stimulation, but it has remained unclear whether transplanted astrocytes are able to clear deposited human Aβ in vivo. We transplanted adult mouse astrocytes into the hippocampi of transgenic mice mimicking AD and observed their fate, effects on microglial responses, and Aβ clearance. After 2-months follow-up time, we discovered a significant reduction in Aβ burden compared with AD mice infused with PBS only. The remaining Aβ deposits were fragmented and most of the Aβ immunoreactivity was seen within the transplanted astrocytes. Concomitant to Aβ reduction, both CD68 and CD45 immunoreactivities were significantly upregulated but phagocytic microglia were often surrounding and engulfing Aβ burdened, TUNEL-positive astrocytes rather than co-localizing with Aβ alone. Astrocytes are known to degrade Aβ also by secreting proteases involved in Aβ catabolism. To study the contribution of neprilysin (NEP), angiotensin-converting enzyme-1 (ACE-1), and endothelin-converting enzyme-2 (ECE-2) in human Aβ clearance, we utilized an ex vivo assay to demonstrate that adult astrocytes respond to human Aβ by upregulating NEP expression. Further, incubation of adult astrocytes with known inhibitors of NEP, ACE-1, or ECE-2 significantly inhibited the removal of human Aβ from the tissue suggesting an important role for these proteases in Aβ clearance by adult astrocytes ex vivo.

Astrocytes in Neurodegenerative Disease: Table 1.

“…Astrocytes plated on Ab-bearing brain sections from an AD mouse model associate with the Ab deposits, which correlated with a decrease in Ab levels (WyssCoray et al 2003;Koistinaho et al 2004). In addition, fluorescently labeled astrocytes transplanted into an AD mouse model migrate to and internalize deposited Ab (Pihlaja et al 2008), and wild-type (WT) astrocytes transplanted into AD mouse brains can clear Ab plaques (Pihlaja et al 2011). Consistent with these observations, Ab-associated tissue damage correlates with both the amount of Ab that accumulates in astrocytes as well as the extent of reactive gliosis (Nagele et al 2003(Nagele et al , 2004Simpson et al 2010).…”

Immunomodulation by interleukin-33 is protective in stroke through modulation of inflammation

“…Adult astrocyte cultures were prepared as described previously (Pihlaja et al, 2011) with some modifications. Briefly, cortices were isolated from 6-8-week-old C57Bl/6 J mice and the tissue was suspended in Hank's Balanced Salt Solution (Lonza) and centrifuged at 1500 rpm for 5 min at RT.…”

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

“…Similarly to microglia, reactive astrocytes surround and engage Aβ senile plaques, contributing to neuroinflammation via releasing cytokines, chemokines, and nitric oxide [130,[161][162][163]. Just like microglia, astrocytes express intra-and extracellular Aβ-degrading enzymatic apparatus upon exposure to Aβ [164]. Furthermore, they also internalize and degrade Aβ, with astroglial ApoE playing crucial roles in both astroglia-and microgliamediated Aβ clearance among experimental conditions [165][166][167][168].…”