**Author details**

Yuhki Saito, Takahide Matsushima and Toshiharu Suzuki

Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido Univer‐ sity, Sapporo, Japan

## **References**

**Figure 10.** Possible role of APP CTF phosphorylation at Thr668 in regulating its fluidity within the membrane and its

X11L abundantly present in non-DRM traps APP outside of the DRM and prevents contact between APP and the β-secretases located within the DRM. Phosphorylation of APP at Thr668 induces conformational changes to the APP cytoplasmic domain and reduces the af‐ finity of the APP C terminal to lipids. This change alters APP CTF fluidity and decreases the probability of APP CTF presence in lipid rafts, in which contact between APP CTFs and γsecretase occurs. In conclusion, translocation of APP and APP CTFs to lipid rafts is regulat‐

ed by neuronal adaptor protein X11L and Thr668 phosphorylation of APP CTFs.

cleavage by γ-secretase.

34 Understanding Alzheimer's Disease

**6. Conclusions**


β-Precursor Protein (APP) C-terminal Fragments is Regulated by Phosphorylation of the Cytoplasmic Thr668 Residue. J Biol Chem 2012; 287(23): 19715-24.

[19] Sano Y, Syuzo Takabatake A, Nakaya T, Saito Y, Tomita S, Itohara S, Suzuki T. En‐ hanced amyloidogenic metabolism of the amyloid beta-protein precursor in the

Mechanism of Alzheimer Amyloid β-Protein Precursor Localization to Membrane Lipid Rafts

http://dx.doi.org/10.5772/54096

37

[20] Kondo M, Shiono M, Itoh G, Takei N, Matsushima T, Maeda M, Taru H, Hata S, Ya‐ mamoto T, Saito Y, Suzuki T. Increased amyloidogenic processing of transgenic hu‐

[21] Lee JH, Lau KF, Perkinton MS, Standen CL, Shemilt SJ, Mercken L, Cooper JD, McLoughlin DM, Miller CC. The neuronal adaptor protein X11alpha reduces Abeta levels in the brains of Alzheimer's APPswe Tg2576 transgenic mice. J Biol Chem

[22] Lee JH, Lau KF, Perkinton MS, Standen CL, Rogelj B, Falinska A, McLoughlin DM, Miller CC. The neuronal adaptor protein X11beta reduces amyloid beta-protein lev‐ els and amyloid plaque formation in the brains of transgenic mice. J Biol Chem

[23] Wahrle S, Das P, Nyborg AC, McLendon C, Shoji M, Kawarabayashi T, Younkin LH, Younkin SG,. Golde TE. Cholesterol-dependent gamma-secretase activity in buoyant

[24] Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, Nukina N, Wong PC, Xu H, Thinakar‐ an G. Association of gamma-secretase with lipid rafts in post-Golgi and endosome

[25] Beel AJ, Mobley CK, Kim HJ, Tian F, Hadziselimovic A, Jap B, Prestegard JH, Sand‐ ers CR. Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor? Biochemistry

[26] Ramelot TA, Nicholson LK. Phosphorylation-induced structural changes in the amy‐ loid precursor protein cytoplasmic tail detected by NMR. J Mol Biol 2001; 307(3):

[27] Sumioka A, Yan D, Tomita S. TARP phosphorylation regulates synaptic AMPA re‐

[28] Gu Y, Misonou H, Sato T, Dohmae N, Takio K, Ihara Y. Distinct intramembrane cleavage of the beta-amyloid precursor protein family resembling gamma-secretase-

[29] Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Hori‐ koshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y. Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-

cholesterol-rich membrane microdomains. Neurobiol Dis 2002;9(1): 11-23.

membranes. J Biol Chem 2004;279(43): 44945-54.

ceptors through lipid bilayers. Neuron 2010; 66(5): 755-67.

like cleavage of Notch. J Biol Chem 2001;276(38): 35235-38.

secretase. J Neurosci 2005; 25(2): 436-45.

man APP in X11-like deficient mouse brain. Mol Neurodegener 2010; 15;5:35.

X11L-deficient mouse brain. J Biol Chem 2006;281(49): 37853-37860.

2003; 278(47): 47025-29.

2004;279(47): 49099-104.

2008; 47(36): 9428-46.

871-884.


[19] Sano Y, Syuzo Takabatake A, Nakaya T, Saito Y, Tomita S, Itohara S, Suzuki T. En‐ hanced amyloidogenic metabolism of the amyloid beta-protein precursor in the X11L-deficient mouse brain. J Biol Chem 2006;281(49): 37853-37860.

β-Precursor Protein (APP) C-terminal Fragments is Regulated by Phosphorylation of

[8] Thinakaran G and Koo EM. Amyloid precursor protein trafficking, processing and

[9] Ramelot TA, Gentile LN, Nicholson LK. Transient structure of the amyloid precursor protein cytoplasmic tail indicates preordering of structure for binding to cytosolic

[10] Ando K, Oishi M, Takeda S, Iijima K, Isohara T, Nairn AC, Kirino Y, Greengard P, Suzuki T. Role of phosphorylation of Alzheimer's amyloid precursor protein during

[11] Hancock JF. Lipid rafts: contentious only from simplistic standpoints. Nat Rev Mol

[12] Brown DA, London E. Functions of lipid rafts in biological membranes. Annu Rev

[13] Benjannet S, Elagoz A, Wickham L, Mamarbachi M, Munzer JS, Basak A, Lazure C, Cromlish JA, Sisodia S, Checler F, Chretien M, Seidah NG. Posttranslational process‐ ing of beta-secretase (beta-amyloid-converting enzyme) and its ectodomain shed‐ ding. The pro- and transmembrane/cytosolic domains affect its cellular activity and

[14] Vetrivel KS, Meckler X, Chen Y, Nguyen PD, Seidah NG, Vassar R, Wong PC, Fukata M, Kounnas MZ, Thinakaran G. Alzheimer disease Abeta production in the absence of S-palmitoylation-dependent targeting of BACE1 to lipid rafts, J Biol Chem

[15] Cheng H, Vetrivel KS, Drisdel RC, Meckler X, Gong P, Leem JY, Li T, Carter M, Chen Y, Nguyen P, Iwatsubo T, Tomita T, Wong PC, Green WN, Kounnas MZ, Thinakaran G. S-palmitoylation of gamma-secretase subunits nicastrin and APH-1, J Biol Chem

[16] Tomita S, Ozaki T, Taru H, Oguchi S, Takeda S, Yagi Y, Sakiyama S, Kirino Y, Suzuki T. Interaction of a neuron-specific protein containing PDZ domains with Alzheimer's

[17] Araki Y, Tomita S, Yamaguchi H, Miyagi N, Sumioka A, Kirino Y, Suzuki T. Novel cadherin-related membrane proteins, Alcadeins, enhance the X11-like protein-medi‐ ated stabilization of amyloid beta-protein precursor metabolism. J Biol Chem 2003;

[18] Taru H, Suzuki T. Regulation of the physiological function and metabolism of AβPP

the Cytoplasmic Thr668 Residue. J Biol Chem 2012; 287(23): 19715-24.

function. J. Biol. Chem. 2008; 283 (44): 29615-29619.

neuronal differentiation. J Neurosci 1999;19(11): 4421-7.

amyloid-beta production, J Biol Chem 2001;276(14): 10879–87.

amyloid precursor protein. J Biol Chem 1999; 274(4): 2243-54.

by AβPP binding proteins. J Alzheimers Dis 2009;18(2): 253-265.

factors. Biochemistry 2000;39(10): 2714-25.

Cell Biol 2006;7(6): 456-62.

36 Understanding Alzheimer's Disease

Cell Dev Biol 1998;14: 111-36.

2009;284 (6): 3793–803.

2009;284(3): 1373–84.

278(49): 49448-49458.


**Chapter 3**

**The Amyloidogenic Pathway Meets**

Daniel A. Bórquez, Ismael Palacios and

Additional information is available at the end of the chapter

due to decreased reelin promoter methylation [10-11].

Christian González-Billault

http://dx.doi.org/10.5772/54038

but at low concentrations [1].

**1. Introduction**

**the Reelin Signaling Cascade: A Cytoskeleton Bridge**

**Between Neurodevelopment and Neurodegeneration**

Reelin is an extracellular matrix glycoprotein of ~400 kD, expressed in mammals during neurodevelopment by the Cajal-Retzius (CR) neurons, which are located in the marginal zone of the cortex and hippocampus [1], and by the cerebellar granule cells [2]. In adult stages, CR neurons degenerate in both structures [3], limiting Reelin production and se‐ cretion to GABAergic interneurons [4]. Meanwhile, the expression in the cerebellum re‐ mains being exclusive of granule cells [5]. During development, Reelin synthesis also occurs in structures like the hypothalamus, the olfactory bulb, the basal ganglia and the amygdale. In these last two brain regions, Reelin expression continues into adulthood

Reelin gene encompasses 450 kb of genomic DNA located on human chromosome 7q22 and in murine chromosome 5. Both genes contain 65 exons that encode a protein sharing a 94,2 (%) of identity [6-7]. The transcription initiation region and the exon 1 of the reelin gene is enriched in CG nucleotides, forming a large CpG island [8], which is associated with a meth‐ ylation-dependent negative regulation of reelin transcription [9]. In fact, DNA methyltrans‐ ferases and histone deacetylases inhibitors increase Reelin protein expression, most likely

In addition to the epigenetic regulation, reelin gene show multiple *cis* elements, which con‐ tain binding sites for transcription factors involved in neurodevelopment such as Sp1, Tbr-1 and Pax6, and elements involved in cytoplasm-to-nucleus signal transduction as CREB and NF-κB [7,12]. Tbr-1 deficient mice show a clear disruption of cortical organization, accompa‐

and reproduction in any medium, provided the original work is properly cited.

© 2013 Bórquez et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,
