In this paper, Verghese et al. provide important data confirming earlier studies showing reduced cellular association between Aβ and astrocytes in the presence of ApoE. The current data obtained from studies on rodent astrocytes suggest competing effects of ApoE on the astrocytic uptake of soluble Aβ. These findings are perfectly in line with our previous findings demonstrating a significant reduction in Aβ uptake by primary human adult astrocytes in vitro (1). We suggested that ApoE interferes with astrocytic uptake of oligomeric, but not fibrillar, preparations of Aβ, as astrocytic uptake of fibrillar Aβ appeared unaffected in the presence of ApoE. Verghese et al. now confirm the notion that uptake of soluble forms of Aβ is decreased in the presence of ApoE; however, they did not address whether ApoE also interferes with astrocytic uptake of fibrillar Aβ. In fact, a reduction of soluble Aβ uptake could possibly be due to ApoE chaperone effects on Aβ, yielding more fibrillar Aβ, which decreases astrocytic Aβ uptake as suggested by earlier findings (1).

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In this paper, Verghese et al. provide important data confirming earlier studies showing reduced cellular association between Aβ and astrocytes in the presence of ApoE. The current data obtained from studies on rodent astrocytes suggest competing effects of ApoE on the astrocytic uptake of soluble Aβ. These findings are perfectly in line with our previous findings demonstrating a significant reduction in Aβ uptake by primary human adult astrocytes in vitro (1). We suggested that ApoE interferes with astrocytic uptake of oligomeric, but not fibrillar, preparations of Aβ, as astrocytic uptake of fibrillar Aβ appeared unaffected in the presence of ApoE. Verghese et al. now confirm the notion that uptake of soluble forms of Aβ is decreased in the presence of ApoE; however, they did not address whether ApoE also interferes with astrocytic uptake of fibrillar Aβ. In fact, a reduction of soluble Aβ uptake could possibly be due to ApoE chaperone effects on Aβ, yielding more fibrillar Aβ, which decreases astrocytic Aβ uptake as suggested by earlier findings (1).

Interestingly, uptake of mutant Aβ also appears to be hampered by ApoE. Bruinsma et al. previously showed that ApoE-conditioned culture media from ApoE3/3 primary human pericytes completely abolished the cell association and internalization of Aβ with the Dutch mutation (Aβ Glu22Gln; D-Aβ1-40) by both primary human pericytes and astrocytes (2).

Last, in regard to the findings presented by Verghese et al., suggesting LRP1 as a receptor candidate mediating astrocytic Aβ internalization in rodent cells, Wilhelmus and coworkers have shown that LRP1 may mediate Aβ uptake and toxicity in primary human brain pericytes, but not in human astrocytes (3). Thus, the contribution of LRP1 to astrocytic Aβ uptake remains elusive before confirming the results of Verghese et al., either in human primary astrocytes or in well-characterized rodent primary astrocyte cultures, both devoid of pericytes. Species-dependent differences in astrocyte functional competence between human and rodent cells have earlier been described (4,5), and these potential differences also need to be ruled out before attributing to LRP1 the role of an astrocytic Aβ receptor with Aβ and ApoE as competing ligands.

References:
1. Nielsen HM, Mulder SD, Musters RJP, Beliën JAM, Eikelenboom P, et al. (2010) Astrocytic Abeta1-42 uptake is determined by Abeta-aggregation state and the presence of amyloid-associated proteins. Glia 58: 1235-1246. Abstract

2. Bruinsma IB, Wilhelmus MM, Kox M, Veerhuis R, de Waal RM, et al. (2010) Apolipoprotein E protects cultured pericytes and astrocytes from D-Abeta(1-40)-mediated cell death. Brain research 1315: 169-180. Abstract

3. Wilhelmus MM, Otte-Holler I, van Triel JJ, Veerhuis R, Maat-Schieman ML, et al. (2007) Lipoprotein receptor-related protein-1 mediates amyloid-beta-mediated cell death of cerebrovascular cells. Am J Pathol 171: 1989-1999. Abstract

4. Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29: 547-553. Abstract

5. Oberheim NA, Takano T, Han X, He W, Lin JH, et al. (2009) Uniquely hominid features of adult human astrocytes. The Journal of neuroscience : the official journal of the Society for Neuroscience 29: 3276-3287. Abstract

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