The Proteome of Human Amyloid Beta Oligomers

Amyloid beta (Aβ) oligomers are thought to play
an important
role during development and progression of Alzheimer’s disease
(AD). Previously, we determined the Aβ oligomer concentrations
in various AD mouse models and in human brain tissues of former AD
patients. Here, we investigate which proteins are part of these Aβ
oligomers, apart from Aβ itself. Because several oligomer-associated
proteins have been implicated in mechanisms leading to AD pathology,
identification of the Aβ oligomer proteome may provide insights
into the formation of Aβ oligomers in vivo and
may reveal novel targets for disease-modifying therapeutic approaches.
Here, we separated different native Aβ assemblies in brain homogenates
of transgenic (tg) AD mice and human AD post mortem samples by density gradient centrifugation, then isolated Aβ-containing
assemblies by co-immunoprecipitation. Mass spectrometry of immunoprecipitated
proteins with label-free quantification (LFQ) showed significant changes
between the proteomes of Aβ oligomers from tg AD mice and wildtype
(wt) mice, confirming some proteins that have been expected to bind
Aβ species, like ApoE and Clusterin, but also indicating novel,
so far unknown, protein content of Aβ oligomers, such as the
RabGAP Tbc1d10b. Some of the hereby identified proteins, like, for
example, Clusterin, were also found to be enriched in Aβ oligomers
from human AD brain tissue derived homogenates as compared to brain
tissue from non-demented controls (NC). Others, such as Netrin-1,
were specifically enriched in Aβ oligomers in AD compared to
NC samples, but not in mouse samples.