The study by Liu et al. shines a new light on the connection between cholesterol metabolism and APP processing. However, at this time the story is reversed—now it appears that APP proteolytic fragments are regulating cholesterol levels in brain and inside the cells. In a series of elegant experiments, the authors describe a mechanism by which the C-terminal fragment of APP, named AICD, modulates brain ApoE and cholesterol metabolism by directly regulating the expression and function of the lipoprotein receptor LRP1. Knocking out APP/APLP2 or components of the γ-secretase complex significantly affected the expression of LRP1, as well as ApoE and intracellular cholesterol levels. These alterations were partially restored by forced expression of AICD. Finally, Liu et al. provide evidence that deletion of LRP1 in forebrain neurons of adult mice significantly increased ApoE levels, while cholesterol levels were conversely decreased.

What makes this study powerful is that, to confirm their in-vitro findings, the authors have used numerous mutated cell lines, including APP/APPL2-DKO...  Read more

The study by Liu et al. shines a new light on the connection between cholesterol metabolism and APP processing. However, at this time the story is reversed—now it appears that APP proteolytic fragments are regulating cholesterol levels in brain and inside the cells. In a series of elegant experiments, the authors describe a mechanism by which the C-terminal fragment of APP, named AICD, modulates brain ApoE and cholesterol metabolism by directly regulating the expression and function of the lipoprotein receptor LRP1. Knocking out APP/APLP2 or components of the γ-secretase complex significantly affected the expression of LRP1, as well as ApoE and intracellular cholesterol levels. These alterations were partially restored by forced expression of AICD. Finally, Liu et al. provide evidence that deletion of LRP1 in forebrain neurons of adult mice significantly increased ApoE levels, while cholesterol levels were conversely decreased.

What makes this study powerful is that, to confirm their in-vitro findings, the authors have used numerous mutated cell lines, including APP/APPL2-DKO and PS1/PS2-DKO primary cells, as well as several lines of knockout mice. As the authors suggest, a possible overall explanation is that the altered expression of LRP significantly affects the catabolism of ApoE, eventually affecting intracellular cholesterol concentration. It is well known that the neuronal uptake of ApoE particles, and possibly ApoE uptake by other cells in brain, is mediated by lipoprotein receptors of the LDLR family (1). Interestingly, in other studies, brain cholesterol levels were not affected in mice with targeted disruption of genes directly related to cholesterol transport and metabolism such as Abca1, LDRL, and, most importantly, ApoE (2-5). In this connection, it would be worth knowing what effect AICD has on the level and lipidation of ApoE-containing lipoproteins in CSF and lipoproteins secreted in the conditioned media of astrocytes isolated from APP/APPL2-DKO or LRP1 KO mice.

Some questions require further investigation. Because LRP1 and ApoE affect Aβ clearance (6-8), it is important to reveal how the lack of LRP1 in LRP1 knockout mice or the suppression of LRP1 expression by γ-secretase inhibitors would affect this process. Most importantly, and relevant to AD, it is interesting to see how the familial mutations of presenilin that increase AICD would affect LRP1 expression and ApoE/cholesterol metabolism.

References:
1. Herz J, Bock HH. Lipoprotein receptors in the nervous system. Annu Rev Biochem. 2002;71:405-34. Epub 2001 Nov 9. Review. Abstract

2. Han X, Cheng H, Fryer JD, Fagan AM, Holtzman DM. Novel role for apolipoprotein E in the central nervous system. Modulation of sulfatide content. J Biol Chem. 2003 Mar 7;278(10):8043-51. Epub 2002 Dec 24. Abstract

3. Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM. ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem. 2004 Sep 24;279(39):40987-93. Epub 2004 Jul 21. Abstract

4. Elder GA, Cho JY, English DF, Franciosi S, Schmeidler J, Sosa MA, Gasperi RD, Fisher EA, Mathews PM, Haroutunian V, Buxbaum JD. Elevated plasma cholesterol does not affect brain Abeta in mice lacking the low-density lipoprotein receptor. J Neurochem. 2007 Aug;102(4):1220-31. Epub 2007 Apr 30. Abstract

5. Fryer JD, Demattos RB, McCormick LM, O'Dell MA, Spinner ML, Bales KR, Paul SM, Sullivan PM, Parsadanian M, Bu G, Holtzman DM. The low density lipoprotein receptor regulates the level of central nervous system human and murine apolipoprotein E but does not modify amyloid plaque pathology in PDAPP mice. J Biol Chem. 2005 Jul 8;280(27):25754-9. Epub 2005 May 11. Abstract

6. Koistinaho M, Lin S, Wu X, Esterman M, Koger D, Hanson J, Higgs R, Liu F, Malkani S, Bales KR, Paul SM. Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med. 2004 Jul 1 ; 10(7):719-26. Abstract

7. Sagare A, Deane R, Bell RD, Johnson B, Hamm K, Pendu R, Marky A, Lenting PJ, Wu Z, Zarcone T, Goate A, Mayo K, Perlmutter D, Coma M, Zhong Z, Zlokovic BV. Clearance of amyloid-beta by circulating lipoprotein receptors. Nat Med. 2007 Sep;13(9):1029-31. Epub 2007 Aug 12. Abstract

8. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest. 2000 Dec;106(12):1489-99. Abstract

View all comments by Radosveta Koldamova

AICD Rules!
Coming on the heels of the report that AICD represses transcription of EGF-receptor (see Zhang et al., 2007), this paper now demonstrates that AICD also represses transcription of LRP1. The role of AICD as a transcriptional regulator had its share of skeptics (Hébert et al., 2006), but together the two studies convincingly support the role of AICD as it was conceived originally (Cao and Sudhof, 2001; Gao and Pimplikar, 2001). In the present studies, Liu et al. used multiple approaches to show that AICD indeed modulates LRP1 expression at the transcriptional level.

The significance of these observations in terms of AD pathogenesis is unclear and needs future studies. Nonetheless, it is becoming clear that AICD, long neglected in favor of its Aβ cousin, is finally commanding attention, and respect, in its own right. The amyloid hypothesis tries to explain, not always...  Read more

AICD Rules!
Coming on the heels of the report that AICD represses transcription of EGF-receptor (see Zhang et al., 2007), this paper now demonstrates that AICD also represses transcription of LRP1. The role of AICD as a transcriptional regulator had its share of skeptics (Hébert et al., 2006), but together the two studies convincingly support the role of AICD as it was conceived originally (Cao and Sudhof, 2001; Gao and Pimplikar, 2001). In the present studies, Liu et al. used multiple approaches to show that AICD indeed modulates LRP1 expression at the transcriptional level.

The significance of these observations in terms of AD pathogenesis is unclear and needs future studies. Nonetheless, it is becoming clear that AICD, long neglected in favor of its Aβ cousin, is finally commanding attention, and respect, in its own right. The amyloid hypothesis tries to explain, not always satisfactorily, the origin of the AD pathology in terms of Aβ. While it is premature to claim that AICD plays a role in AD pathogenesis, the observations of Liu et al. present a linkage between APP processing and ApoE/cholesterol metabolism that does not go through Aβ but through AICD. Indeed, AICD alone, without Aβ, affects other parameters that feature prominently in AD. AICD activates GSK3β without involving Aβ (Ryan and Pimplikar, 2005), and a recent study from Karen Ashe's group (Ma et al., 2007) implicated AICD in enhanced memory and synaptic plasticity. Finally, the D664A mouse created by Dale Bredesen and colleagues shows that APP-CTF is pivotal in AD pathogenesis (Galvan et al., 2006; Saganich et al., 2006). Although these data were interpreted in terms of inhibition of cleavage of APP-CTF by caspases, it is quite likely that D664A-AICD is simply “dysfunctional.” In any case, it is no longer prudent—or possible—to ignore AICD when talking about APP function or AD pathology.

Although Liu et al. show a fairly strong connection between APP and LRP1 expression through AICD, the link between APP-LRP1 and altered cholesterol metabolism may be a red herring. Liu et al. find that AICD does not affect LDLR1 expression, so the effects on cholesterol uptake and catabolism by neurons are likely to be less pronounced. LRP1 is thought to mediate intracellular signaling kinases through ApoE binding or APP interaction (Rebeck et al., 2006). Moreover, several studies have shown LRP1 to modulate APP levels and APP-processing. Thus, it is not a given that APP-LRP1 interplay involves cholesterol homeostasis.

View all comments by Sanjay W. Pimplikar

The work by Bu et al. significantly—and elegantly—extends our understanding of the role of APP metabolism in lipid regulation. Their experiments clearly show that γ-secretase-mediated processing of APP regulates LRP1 transcription and hence one essential aspect of cellular cholesterol (and general lipid) homeostasis. AICD expression in APP or PS knockouts nicely restored LRP1 regulation and partly rescued the damaged cellular lipid homeostasis, thus identifying a role for AICD in LRP1 transcription control. Point mutations in AICD further support this interpretation.

It is tempting to speculate that Aβ40 (as downregulator of the cholesterol synthesis enzyme HMGR) together with AICD (as a regulator of cholesterol uptake via LRP1) might be able to rescue cellular cholesterol levels fully. However, lipid homeostasis is a fairly complex game, and more players might be involved. Interestingly, Bu and colleagues report that PS1, but not PS2, is involved in LRP1 regulation. For sphingomyelin metabolism (a function of Aβ42), this is different. Here PS2 is able to functionally...  Read more

The work by Bu et al. significantly—and elegantly—extends our understanding of the role of APP metabolism in lipid regulation. Their experiments clearly show that γ-secretase-mediated processing of APP regulates LRP1 transcription and hence one essential aspect of cellular cholesterol (and general lipid) homeostasis. AICD expression in APP or PS knockouts nicely restored LRP1 regulation and partly rescued the damaged cellular lipid homeostasis, thus identifying a role for AICD in LRP1 transcription control. Point mutations in AICD further support this interpretation.

It is tempting to speculate that Aβ40 (as downregulator of the cholesterol synthesis enzyme HMGR) together with AICD (as a regulator of cholesterol uptake via LRP1) might be able to rescue cellular cholesterol levels fully. However, lipid homeostasis is a fairly complex game, and more players might be involved. Interestingly, Bu and colleagues report that PS1, but not PS2, is involved in LRP1 regulation. For sphingomyelin metabolism (a function of Aβ42), this is different. Here PS2 is able to functionally replace PS1.

It should be kept in mind that several type 1 membrane receptors contain actual or putative γ-secretase cleavage domains. This complicates the potential mechanism as much as it causes difficulties in the interpretation of the data. LRP is but one such example. Bu et al. also tested different AICD constructs and found no functional differences for these constructs. This, too, is remarkable, because for Aβ peptides the C-terminus is essential to determine whether the peptide’s activity is directed toward cholesterol or sphingomyelin.

For those familiar with lipid homeostasis, all of this is déjà vu. It very closely resembles another system for cholesterol homeostasis—the SREBPs. SREBP processing and signaling is very complex and still far from being completely understood. It therefore does not require the art of prophecy to predict that it will take many more publications until the role of APP processing and lipid homeostasis is fully understood. One can only hope that these will be of the same high quality as the work presented here by Bu and colleagues.

View all comments by Marcus O. W. Grimm
View all comments by Tobias Hartmann