Alzheimer’s
2008/6/13
J Neurochem. 2005
Nov;95(4):1059-68. Epub
2005 Sep 7. Holback S, Adlerz L, Iverfeldt K. Department
of Neurochemistry, The amyloid
precursor protein (APP) belongs to a conserved gene family, also including
the amyloid precursor-like proteins, APLP1 and
APLP2. We have previously shown that all members of the APP protein family
are up-regulated upon retinoic acid (RA)-induced neuronal differentiation
of SH-SY5Y neuroblastoma cells. Here, we
demonstrate that RA also affects the processing of APLP2 and APP, as shown
by increased shedding of both sAPLP2 and sAPPalpha,
as well as elevated levels of the APP intracellular domains (AICDs). Brain-derived neurotrophic
factor (BDNF) has been reported to induce APP promoter activity and RA
induces expression of the tyrosine kinase
receptor B (TrkB) in neuroblastoma
cells. We show that the increase in shedding of both APLP2 and APP in
response to RA is not mediated through the TrkB
receptor. However, BDNF concomitant with RA increased the expression of APP
even further. In addition, the secretion of sAPLP2 and sAPPalpha
as well as the levels of AICDs were increased in
response to BDNF. In contrast, the levels of membrane-bound APP C-terminal
fragment C99 significantly decreased. Our results suggest that RA and BDNF shifts APP processing towards the alpha-secretase pathway. In addition, we show that RA and
BDNF regulate N-linked glycosylation of APLP1. PMID: 16150056 [PubMed
- indexed for MEDLINE] J Biol Chem. 2005 Dec 23;280(51):41987-96.
Epub 2005 Oct 19. gamma-Secretase substrate selectivity can be modulated directly
via interaction with a nucleotide-binding site. Proc
Natl Acad Sci U S A. 2006 May 2;103(18):7130-5.
Epub 2006 Apr 25.
Increased processing of APLP2
and APP with concomitant formation of APP intracellular domains in BDNF and
retinoic acid-differentiated human neuroblastoma
cells.
Fraering PC, Ye
W, LaVoie MJ, Ostaszewski BL, Selkoe DJ, Wolfe
MS.
Center for Neurologic Diseases,
Brigham & Women's Hospital and
gamma-Secretase is an
unusual protease with an intramembrane catalytic
site that cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta)
precursor (APP) and the Notch receptor. Genetic and biochemical studies
have identified four membrane proteins as components of gamma-secretase: heterodimeric presenilin composed of its N- and C-terminal fragments,
nicastrin, Aph-1, and Pen-2. Here we demonstrated
that certain compounds, including protein kinase
inhibitors and their derivatives, act directly on purified gamma-secretase to selectively block cleavage of APP- but not
Notch-based substrates. Moreover, ATP activated the generation of the APP
intracellular domain and Abeta, but not the
generation of the Notch intracellular domain by the purified protease
complex, and was a direct competitor of the APP-selective inhibitors, as
were other nucleotides. In accord, purified gamma-secretase
bound specifically to an ATP-linked resin. Finally, a photoactivable
ATP analog specifically labeled presenilin
1-C-terminal fragments in purified gamma-secretase
preparations; the labeling was blocked by ATP itself and APP-selective
gamma-secretase inhibitors. We concluded that a
nucleotide-binding site exists within gamma-secretase,
and certain compounds that bind to this site can specifically modulate the
generation of Abeta while sparing Notch. Drugs
targeting the gamma-secretase nucleotide-binding
site represent an attractive strategy for safely treating Alzheimer
disease.
PMID: 16236717 [PubMed - indexed for MEDLINE]
Reversal of
Alzheimer's-like pathology and behavior in human APP transgenic mice by
mutation of Asp664.
Galvan
V, Gorostiza OF, Banwait S, Ataie M, Logvinova AV, Sitaraman S, Carlson
E, Sagi SA, Chevallier N, Jin
K, Greenberg
DA, Bredesen DE.
*Buck Institute for Age Research,
The deficits characteristic of Alzheimer's disease (AD) are believed to
result, at least in part, from the neurotoxic
effects of beta-amyloid peptides, a set of 39-43
amino acid fragments derived proteolytically from
beta-amyloid precursor protein (APP). APP also is
cleaved intracytoplasmically at Asp-664 to
generate a second cytotoxic peptide, APP-C31, but
whether this C-terminal processing of APP plays a role in the pathogenesis
of AD is unknown. Therefore, we compared elements of the Alzheimer's
phenotype in transgenic mice modeling AD with vs. without a functional
Asp-664 caspase cleavage site. Surprisingly,
whereas beta-amyloid production and plaque
formation were unaltered, synaptic loss, astrogliosis,
dentate gyral atrophy, increased neuronal
precursor proliferation, and behavioral abnormalities were completely
prevented by a mutation at Asp-664. These results suggest that Asp-664
plays a critical role in the generation of Alzheimer-related pathophysiological and behavioral changes in human APP
transgenic mice, possibly as a cleavage site or via protein-protein
interactions.
PMID: 16641106 [PubMed - in process]