[Abstract Title]. - Society for Neuroscience

Authors: M. ELIAVA 1 , *V. GRINEVICH 4 , P. N. LACOR 2 , R. VASSAR 3 , W. L. KLEIN 2 , P.
OSTEN 1 ;
1 Physiol., 2 Neurobio. and Physiol., 3 Cell and Mol. Biol., Northwestern Univ., Chicago, IL; 4 Mol.
Neurobiol., Max Planck Inst. Med. Res., Heidelberg, Germany
Abstract: Soluble amyloid-β (Aβ) oligomers have been proposed to critically contribute to early
pathology of Alzheimer‟s disease (AD), especially to deficits in synaptic plasticity that may
underlie memory impairments. However, whereas the evidence for pathological function of
exogenously applied Aβ oligomers is well documented, little is known about how Aβ oligomers
are formed in the brain. For example, it is not known whether Aβ oligomerization occurs
intraneuronally following β- and γ-secretase-mediated proteolysis of amyloid precursor protein
(APP) or whether Aβ oligomers are formed from secreted Aβ monomers extracellularly. Here we
examine this question in two AD mouse models, 5XFAD mice with rapid Aβ accumulation due
to expression of five FAD mutations (APP Swedish, Florida and London and presenilin-1
M146L and L286V) and Tg2576 mice with much slower Aβ accumulation from expression of a
single APP Swedish FAD mutation. We take advantage of a mosaic expression pattern common
to most transgenic mice and ask whether neurons with high expression of the APP transgene also
show high accumulation of intraneuronal monomeric and oligomeric Aβ, as would be expected
from direct intraneuronal processing. These experiments are done by double-labeling
immunohistochemistry, with 1) APP N- or C-terminal-specific antibodies applied to detect the
level of APP transgene expression, and 2) Aβ40-, Aβ42- and Aβ oligomer-specific antibodies
used to detect the level of intraneuronal accumulation of the respective Aβ forms. Our
preliminary data suggest a close correlation between APP expression and intraneuronal
accumulation of oligomeric Aβ forms. Furthermore, cortical neurons previously shown to be
highly vulnerable to cell death in the 5XFAD model show the highest expression of APP and
accumulation of Aβ oligomers. This suggests that Aβ oligomers formed intraneuronally may
directly contribute to AD neurotoxicity.
Disclosures: M. Eliava, None; V. Grinevich , None; P.N. Lacor, None; R. Vassar,
None; W.L. Klein, None; P. Osten, None.
Poster
243. Abeta Assembly and Deposition
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 243.5/J11
Topic: C.01.b. Abeta assembly and deposition
Support: NIH Grant AG18879