Several papers from the groups of Koo, Rebeck, and Hyman support the existence of a trimeric complex formed by two membrane proteins, the LDL-related receptor LRP and APP, together with the intracellular adaptor protein, Fe65 (1-4). Now, this paper by Bill Rebeck and colleagues demonstrates that a similar tripartite complex exists that includes APP, Fe65, and the ApoE receptor ApoEr2. Knowing the roles of these two trimeric complexes in the regulation of the processing of APP could have a significant impact on the understanding of the molecular mechanisms behind AD.
Hyang-Sook Hoe and colleagues show that, similar to what happens in the case of LRP, Fe65 functions as an intracellular adaptor that enables APP to associate with ApoEr2. At least in COS7 cells, Fe65 overexpression also increases the generation of the soluble forms of APP and ApoEr2, and of the cognate C-terminal fragments (CTFs), while in brain extracts from Fe65 knockout mice, ApoEr2 CTFs are decreased. These results add a new tessera to the observation made by the same group (5) that F-spondin favors the association of APP and ApoEr2, thus working as an extracellular adaptor between the two molecules. This aids accumulation of secreted forms and CTFs of both APP and ApoEr2. On the basis of these observations, it can be hypothesized that Fe65 is involved in driving APP and ApoEr2 to the plasma membrane where the complex is stabilized by F-spondin. This would favor the exposure of the complex to proteolytic enzymes that shed the ectodomains of the two membrane proteins.
A possible crosstalk between the two complexes, APP-Fe65-LRP and APP-Fe65-ApoEr2, seems to emerge from the results shown. In fact, Fe65 overexpression decreases APP-ApoEr2 coimmunoprecipitation in LRP+/+ CHO cells, while it increases the formation of the complex in LRP-/- cells. Accordingly, Fe65 increases soluble APP and CTFs only in the absence of LRP. These findings seem to suggest that LRP and ApoEr2 compete for the binding to Fe65, and in turn for the association with APP. However, the amount of ApoEr2 coimmunoprecipitated with APP is significantly higher in LRP+/+ cells than in LRP-/- cells, suggesting that there is something more to be understood: LRP seems to create conditions that favor the formation (or stabilization) of the APP-Fe65-ApoEr2 complex. An interesting paper by Eddie Koo and colleagues (2) suggested that the effects of Fe65 on the processing of APP are dependent on LRP. Therefore, fluctuations of LRP levels could be responsible for different outcomes of Fe65 overexpression in different cellular contexts (3,6-8). Although we do not know how significant and how different are the fractions of APP bound to either LRP or ApoEr2, considering these new results by Rebeck and coworkers, ApoEr2 should be considered a new player of the game.
While it is easy to suggest other players, it is difficult to put each of them in the right place and to predict their possible role in AD: ApoE is, of course, outside the cell, together with Reelin; Dab1 is inside the cells, interacting with APP or with lipoprotein receptors and possibly competing with Fe65 (or with the Fe65-Mena complex).
References:
Yoon IS, Pietrzik CU, Kang DE, Koo EH.
Sequences from the low density lipoprotein receptor-related protein (LRP) cytoplasmic domain enhance amyloid beta protein production via the beta-secretase pathway without altering amyloid precursor protein/LRP nuclear signaling.
J Biol Chem. 2005 May 20;280(20):20140-7.
PubMed.
Pietrzik CU, Yoon IS, Jaeger S, Busse T, Weggen S, Koo EH.
FE65 constitutes the functional link between the low-density lipoprotein receptor-related protein and the amyloid precursor protein.
J Neurosci. 2004 Apr 28;24(17):4259-65.
PubMed.
Guénette SY, Chang Y, Hyman BT, Tanzi RE, Rebeck GW.
Low-density lipoprotein receptor-related protein levels and endocytic function are reduced by overexpression of the FE65 adaptor protein, FE65L1.
J Neurochem. 2002 Aug;82(4):755-62.
PubMed.
Kinoshita A, Whelan CM, Smith CJ, Mikhailenko I, Rebeck GW, Strickland DK, Hyman BT.
Demonstration by fluorescence resonance energy transfer of two sites of interaction between the low-density lipoprotein receptor-related protein and the amyloid precursor protein: role of the intracellular adapter protein Fe65.
J Neurosci. 2001 Nov 1;21(21):8354-61.
PubMed.
Hoe HS, Wessner D, Beffert U, Becker AG, Matsuoka Y, Rebeck GW.
F-spondin interaction with the apolipoprotein E receptor ApoEr2 affects processing of amyloid precursor protein.
Mol Cell Biol. 2005 Nov;25(21):9259-68.
PubMed.
Guénette SY, Chen J, Ferland A, Haass C, Capell A, Tanzi RE.
hFE65L influences amyloid precursor protein maturation and secretion.
J Neurochem. 1999 Sep;73(3):985-93.
PubMed.
Sabo SL, Lanier LM, Ikin AF, Khorkova O, Sahasrabudhe S, Greengard P, Buxbaum JD.
Regulation of beta-amyloid secretion by FE65, an amyloid protein precursor-binding protein.
J Biol Chem. 1999 Mar 19;274(12):7952-7.
PubMed.
Santiard-Baron D, Langui D, Delehedde M, Delatour B, Schombert B, Touchet N, Tremp G, Paul MF, Blanchard V, Sergeant N, Delacourte A, Duyckaerts C, Pradier L, Mercken L.
Expression of human FE65 in amyloid precursor protein transgenic mice is associated with a reduction in beta-amyloid load.
J Neurochem. 2005 Apr;93(2):330-8.
PubMed.
Comments
Università di Napoli Federico II
Several papers from the groups of Koo, Rebeck, and Hyman support the existence of a trimeric complex formed by two membrane proteins, the LDL-related receptor LRP and APP, together with the intracellular adaptor protein, Fe65 (1-4). Now, this paper by Bill Rebeck and colleagues demonstrates that a similar tripartite complex exists that includes APP, Fe65, and the ApoE receptor ApoEr2. Knowing the roles of these two trimeric complexes in the regulation of the processing of APP could have a significant impact on the understanding of the molecular mechanisms behind AD.
Hyang-Sook Hoe and colleagues show that, similar to what happens in the case of LRP, Fe65 functions as an intracellular adaptor that enables APP to associate with ApoEr2. At least in COS7 cells, Fe65 overexpression also increases the generation of the soluble forms of APP and ApoEr2, and of the cognate C-terminal fragments (CTFs), while in brain extracts from Fe65 knockout mice, ApoEr2 CTFs are decreased. These results add a new tessera to the observation made by the same group (5) that F-spondin favors the association of APP and ApoEr2, thus working as an extracellular adaptor between the two molecules. This aids accumulation of secreted forms and CTFs of both APP and ApoEr2. On the basis of these observations, it can be hypothesized that Fe65 is involved in driving APP and ApoEr2 to the plasma membrane where the complex is stabilized by F-spondin. This would favor the exposure of the complex to proteolytic enzymes that shed the ectodomains of the two membrane proteins.
A possible crosstalk between the two complexes, APP-Fe65-LRP and APP-Fe65-ApoEr2, seems to emerge from the results shown. In fact, Fe65 overexpression decreases APP-ApoEr2 coimmunoprecipitation in LRP+/+ CHO cells, while it increases the formation of the complex in LRP-/- cells. Accordingly, Fe65 increases soluble APP and CTFs only in the absence of LRP. These findings seem to suggest that LRP and ApoEr2 compete for the binding to Fe65, and in turn for the association with APP. However, the amount of ApoEr2 coimmunoprecipitated with APP is significantly higher in LRP+/+ cells than in LRP-/- cells, suggesting that there is something more to be understood: LRP seems to create conditions that favor the formation (or stabilization) of the APP-Fe65-ApoEr2 complex. An interesting paper by Eddie Koo and colleagues (2) suggested that the effects of Fe65 on the processing of APP are dependent on LRP. Therefore, fluctuations of LRP levels could be responsible for different outcomes of Fe65 overexpression in different cellular contexts (3,6-8). Although we do not know how significant and how different are the fractions of APP bound to either LRP or ApoEr2, considering these new results by Rebeck and coworkers, ApoEr2 should be considered a new player of the game.
While it is easy to suggest other players, it is difficult to put each of them in the right place and to predict their possible role in AD: ApoE is, of course, outside the cell, together with Reelin; Dab1 is inside the cells, interacting with APP or with lipoprotein receptors and possibly competing with Fe65 (or with the Fe65-Mena complex).
References:
Yoon IS, Pietrzik CU, Kang DE, Koo EH. Sequences from the low density lipoprotein receptor-related protein (LRP) cytoplasmic domain enhance amyloid beta protein production via the beta-secretase pathway without altering amyloid precursor protein/LRP nuclear signaling. J Biol Chem. 2005 May 20;280(20):20140-7. PubMed.
Pietrzik CU, Yoon IS, Jaeger S, Busse T, Weggen S, Koo EH. FE65 constitutes the functional link between the low-density lipoprotein receptor-related protein and the amyloid precursor protein. J Neurosci. 2004 Apr 28;24(17):4259-65. PubMed.
Guénette SY, Chang Y, Hyman BT, Tanzi RE, Rebeck GW. Low-density lipoprotein receptor-related protein levels and endocytic function are reduced by overexpression of the FE65 adaptor protein, FE65L1. J Neurochem. 2002 Aug;82(4):755-62. PubMed.
Kinoshita A, Whelan CM, Smith CJ, Mikhailenko I, Rebeck GW, Strickland DK, Hyman BT. Demonstration by fluorescence resonance energy transfer of two sites of interaction between the low-density lipoprotein receptor-related protein and the amyloid precursor protein: role of the intracellular adapter protein Fe65. J Neurosci. 2001 Nov 1;21(21):8354-61. PubMed.
Hoe HS, Wessner D, Beffert U, Becker AG, Matsuoka Y, Rebeck GW. F-spondin interaction with the apolipoprotein E receptor ApoEr2 affects processing of amyloid precursor protein. Mol Cell Biol. 2005 Nov;25(21):9259-68. PubMed.
Guénette SY, Chen J, Ferland A, Haass C, Capell A, Tanzi RE. hFE65L influences amyloid precursor protein maturation and secretion. J Neurochem. 1999 Sep;73(3):985-93. PubMed.
Sabo SL, Lanier LM, Ikin AF, Khorkova O, Sahasrabudhe S, Greengard P, Buxbaum JD. Regulation of beta-amyloid secretion by FE65, an amyloid protein precursor-binding protein. J Biol Chem. 1999 Mar 19;274(12):7952-7. PubMed.
Santiard-Baron D, Langui D, Delehedde M, Delatour B, Schombert B, Touchet N, Tremp G, Paul MF, Blanchard V, Sergeant N, Delacourte A, Duyckaerts C, Pradier L, Mercken L. Expression of human FE65 in amyloid precursor protein transgenic mice is associated with a reduction in beta-amyloid load. J Neurochem. 2005 Apr;93(2):330-8. PubMed.
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