Item 1. Changes in Control of Registrant.
On June 27, 1996, at a special meeting of stockhold-
ers, the stockholders of Athena Neurosciences, Inc. (the "Com-
pany") approved and adopted the Agreement and Plan of Merger
dated March 18, 1996, as amended (the "Merger Agreement"),
among Elan Corporation, plc ("Elan"), Elan Acquisition Corp.
("Sub") and the Company, which provided for, among other
things, the merger of Sub with and into the Company (the
"Merger"). The Merger became effective on July 1, 1996, as a
result of which (i) each issued and outstanding share of Common
Stock of the Company (other than shares owned by Elan or any
subsidiary of Elan) was converted into the right to receive
.2956 American Depositary Shares of Elan and (ii) the Company
became an wholly-owned subsidiary of Elan. (snip)
Several SI biofreaks owned Athena.........
J Biol Chem 1996 Jan 19;271(3):1343-8
Differential effects of a Rab6 mutant on secretory versus amyloidogenic
processing of Alzheimer's beta-amyloid precursor protein.
McConlogue L, Castellano F, deWit C, Schenk D, Maltese WA
Athena Neurosciences, South San Francisco, California 94080, USA.
The Ras-related GTP-binding protein, Rab6, is localized in late Golgi compartments where it
mediates intra-Golgi vesicular trafficking. Herein we report that coexpression of Alzheimer's
beta-amyloid precursor protein (beta APP751) with a dominant-negative Rab6 mutant
(Rab6N126I) in human embryonal kidney 293 cells causes an increase in secretion of the soluble
amino-terminal exodomain (s-APP alpha) derived from non-amyloidogenic processing of
beta-APP751 by alpha-secretase. The effect was specific to Rab6N126I, since the
corresponding mutation in Rab8 (i.e. Rab8N121I), which has been implicated in protein
transport to the plasma membrane, caused a modest reduction in s-APP alpha secretion. While
Rab6N126I stimulated secretion of APP alpha, the accumulation of amyloid beta peptide (A
beta) in the medium was either moderately reduced or unaffected. Similar differential effects of
Rab6N126I on secretion of s-APP alpha versus A beta were observed in cell cultures that were
overproducing A beta after transfection with a plasmid encoding Swedish variant of beta
APP751. Moreover, assays of medium from the latter cultures revealed a marked increase in
secretion of s-APP alpha relative to s-APP beta (the immediate product derived from cleavage
of beta APP by beta-secretase). The results indicate that vesicular transport events controlled by
Rab6 occur at or near a critical juncture in the trans-Golgi network where beta APP is sorted
into either the constitutive alpha-secretase pathway or the amyloidogenic beta-secretase
pathway.
Nature 1999 Jul 8;400(6740):173-7
Related Articles, Books, OMIM, LinkOut
Immunization with amyloid-beta attenuates Alzheimer-disease-like
pathology in the PDAPP mouse.
Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J,
Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R,
Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M,
Yednock T, Games D, Seubert P
Elan Pharmaceuticals, South San Francisco, California 94080, USA. dschenk@elanpharma.com
Amyloid-beta peptide (Abeta) seems to have a central role in the neuropathology of Alzheimer's
disease (AD). Familial forms of the disease have been linked to mutations in the amyloid
precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result
in increased production of the 42-amino-acid form of the peptide (Abeta42), which is the
predominant form found in the amyloid plaques of Alzheimer's disease. The PDAPP transgenic
mouse, which overexpresses mutant human APP (in which the amino acid at position 717 is
phenylalanine instead of the normal valine), progressively develops many of the neuropathological
hallmarks of Alzheimer's disease in an age- and brain-region-dependent manner. In the present
study, transgenic animals were immunized with Abeta42, either before the onset of AD-type
neuropathologies (at 6 weeks of age) or at an older age (11 months), when amyloid-beta
deposition and several of the subsequent neuropathological changes were well established. We
report that immunization of the young animals essentially prevented the development of
beta-amyloid-plaque formation, neuritic dystrophy and astrogliosis. Treatment of the older
animals also markedly reduced the extent and progression of these AD-like neuropathologies.
Our results raise the possibility that immunization with amyloid-beta may be effective in preventing
and treating Alzheimer's disease.
J Neurochem 2001 Jan;76(1):173-181
Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels
in brain.
Dovey HF, John V, Anderson JP, Chen LZ, de Saint Andrieu P, Fang LY, Freedman SB,
Folmer B, Goldbach E, Holsztynska EJ, Hu KL, Johnson-Wood KL, Kennedy SL,
Kholodenko D, Knops JE, Latimer LH, Lee M, Liao Z, Lieberburg IM, Motter RN,
Mutter LC, Nietz J, Quinn KP, Sacchi KL, Seubert PA, Shopp GM, Thorsett ED, Tung
JS, Wu J, Yang S, Yin CT, Schenk DB, May PC, Altstiel LD, Bender MH, Boggs LN,
Britton TC, Clemens JC, Czilli DL, Dieckman-McGinty DK, Droste JJ, Fuson KS,
Gitter BD, Hyslop PA, Johnstone EM, Li WY, Little SP, Mabry TE, Miller FD, Ni B,
Nissen JS, Porter WJ, Potts BD, Reel JK, Stephenson D, Su Y, Shipley LA, Whitesitt
CA, Yin T, Audia JE
Elan Pharmaceuticals, Inc., South San Francisco, USA Eli Lilly and Company, Lilly Research
Labs, Lilly Corporate Center, Indianapolis, USA.
[Record supplied by publisher]
Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's
disease. We describe a novel class of compounds that reduce Ass production by functionally
inhibiting gamma-secretase, the activity responsible for the carboxy-terminal cleavage required
for Ass production. These molecules are active in both 293 HEK cells and neuronal cultures, and
exert their effect upon Ass production without affecting protein secretion, most notably in the
secreted forms of the amyloid precursor protein (APP). Oral administration of one of these
compounds, N:-[N:-(3,5-difluorophenacetyl)-L-alanyl]-S:-phenylglycine t-butyl ester, to mice
transgenic for human APP(V717F) reduces brain levels of Ass in a dose-dependent manner
within 3 h. These studies represent the first demonstration of a reduction of brain Ass in vivo.
Development of such novel functional gamma-secretase inhibitors will enable a clinical
examination of the Ass hypothesis that Ass peptide drives the neuropathology observed in
Alzheimer's disease. |
