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3-D structure of BACE
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[Courtesy of Jordan Tang and Lin Hong.]
Crystal structure of BACE-1 (green), bound to experimental inhibitor OM99-2.
[Courtesy of Jordan Tang and Lin Hong.]
Primary Papers
- Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, Zhang XC, Tang J. Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor. Science. 2000 Oct 6;290(5489):150-3. PubMed.
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Structural studies find hexapeptides by which tau aggregates into paired helical filaments
[Courtesy of Eckhard and Eva Maria Mandelkow.]
This diagram summarizes the structural domains of human tau, including two domains (boxed yellow arrows) that nucleate tau aggregation.
Primary Papers
- von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, Mandelkow E. Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5129-34. PubMed.
- Mukrasch MD, Bibow S, Korukottu J, Jeganathan S, Biernat J, Griesinger C, Mandelkow E, Zweckstetter M. Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol. 2009 Feb 17;7(2):e34. PubMed.
Neprilysin and other enzymes degrade Aβ in vivo
[Copyright 2003 Cell Press.]
APP transgenic mice that also overexpress the Aβ-degrading enzymes IDE or neprilysin have a lower plaque burden than controls.
Primary Papers
- Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Kawashima-Morishima M, Lee HJ, Hama E, Sekine-Aizawa Y, Saido TC. Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med. 2000 Feb;6(2):143-50. PubMed.
- Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ. Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. J Neurosci. 2000 Mar 1;20(5):1657-65. PubMed.
- Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, Gerard C, Hama E, Lee HJ, Saido TC. Metabolic regulation of brain Abeta by neprilysin. Science. 2001 May 25;292(5521):1550-2. PubMed.
- Eckman EA, Reed DK, Eckman CB. Degradation of the Alzheimer's amyloid beta peptide by endothelin-converting enzyme. J Biol Chem. 2001 Jul 6;276(27):24540-8. Epub 2001 May 3 PubMed.
- Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, Frosch MP, Selkoe DJ. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003 Dec 18;40(6):1087-93. PubMed.
In AD, both neurons and microglia change expression of immune-related genes
[Copyright 2002 American Society for Investigative Pathology.]
Microglia and endothelial cells in frontal cortex of AD brain express the scavenger receptor CD36. Immunofluorescent staining with anti-CD36 antibody (a, d, g, and j), the microglial marker anti-CD11b antibody in b and h, anti-GFAP in e, and staining with Ricin in k. Overlays of staining in each row c, f, i, l). Cells lining the brain vasculature (likely endothelial cells) (k) express CD36 (j and l) but not the microglial marker Mac-1 (g, h, and i). (From Coraci et al., 2002.)
Primary Papers
- Yang LB, Li R, Meri S, Rogers J, Shen Y. Deficiency of complement defense protein CD59 may contribute to neurodegeneration in Alzheimer's disease. J Neurosci. 2000 Oct 15;20(20):7505-9. PubMed.
- Lue LF, Rydel R, Brigham EF, Yang LB, Hampel H, Murphy GM, Brachova L, Yan SD, Walker DG, Shen Y, Rogers J. Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro. Glia. 2001 Jul;35(1):72-9. PubMed.
- Lue LF, Walker DG, Rogers J. Modeling microglial activation in Alzheimer's disease with human postmortem microglial cultures. Neurobiol Aging. 2001 Nov-Dec;22(6):945-56. PubMed.
- Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, Luster AD, Silverstein SC, El-Khoury JB. CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol. 2002 Jan;160(1):101-12. PubMed.
- Duan RS, Yang X, Chen ZG, Lu MO, Morris C, Winblad B, Zhu J. Decreased fractalkine and increased IP-10 expression in aged brain of APP(swe) transgenic mice. Neurochem Res. 2008 Jun;33(6):1085-9. PubMed.
Midlife hypertension increases risk
[Copyright 2001 BMJ Publishing Group Ltd.]
Association of midlife blood pressure and cholesterol concentrations with Alzheimer's disease later in life. Values are percentages unless otherwise stated. (From Kivipelto et al., 2001.)
Primary Papers
- Launer LJ, Ross GW, Petrovitch H, Masaki K, Foley D, White LR, Havlik RJ. Midlife blood pressure and dementia: the Honolulu-Asia aging study. Neurobiol Aging. 2000 Jan-Feb;21(1):49-55. PubMed.
- Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ. 2001 Jun 16;322(7300):1447-51. PubMed.
Further Reading
News
First mice expressing FTD tau mutations
Primary Papers
- Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet. 2000 Aug;25(4):402-5. PubMed.
- Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K, Yoshida H, Holzer M, Craxton M, Emson PC, Atzori C, Migheli A, Crowther RA, Ghetti B, Spillantini MG, Goedert M. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci. 2002 Nov 1;22(21):9340-51. PubMed.
Primary Links
- hTau.P301S mouse
- JNPL3(P301L) mouse
Further Reading
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Galantamine approved
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