3 research outputs found
Multimodal Chemical Imaging of Amyloid Plaque Polymorphism Reveals Aβ Aggregation Dependent Anionic Lipid Accumulations and Metabolism
Amyloid plaque formation
constitutes one of the main pathological
hallmarks of Alzheimer’s disease (AD) and is suggested to be
a critical factor driving disease pathogenesis. Interestingly, in
patients that display amyloid pathology but remain cognitively normal,
Aβ deposits are predominantly of diffuse morphology suggesting
that cored plaque formation is primarily associated with cognitive
deterioration and AD pathogenesis. Little is known about the molecular
mechanism responsible for conversion of monomeric Aβ into neurotoxic
aggregates and the predominantly cored deposits observed in AD. The
structural diversity among Aβ plaques, including cored/compact-
and diffuse, may be linked to their distinct Aβ profile and
other chemical species including neuronal lipids. We developed a novel,
chemical imaging paradigm combining matrix assisted laser desorption/ionization
imaging mass spectrometry (MALDI IMS) and fluorescent amyloid staining.
This multimodal imaging approach was used to probe the lipid chemistry
associated with structural plaque heterogeneity in transgenic AD mice
(tgAPP<sub>Swe</sub>) and was correlated to Aβ profiles determined
by subsequent laser microdissection and immunoprecipitation-mass spectrometry.
Multivariate image analysis revealed an inverse localization of ceramides
and their matching metabolites to diffuse and cored structures within
single plaques, respectively. Moreover, phosphatidylinositols implicated
in AD pathogenesis, were found to localize to the diffuse Aβ
structures and correlate with Aβ1–42. Further, lysophospholipids
implicated in neuroinflammation were increased in all Aβ deposits.
The results support previous clinical findings on the importance of
lipid disturbances in AD pathophysiology and associated sphingolipid
processing. These data highlight the potential of multimodal imaging
as a powerful technology to probe neuropathological mechanisms
Evidence for Age-Dependent <i>in Vivo</i> Conformational Rearrangement within Aβ Amyloid Deposits
Deposition
of aggregated Aβ peptide in the brain is one of the major hallmarks
of Alzheimer’s disease. Using a combination of two structurally
different, but related, hypersensitive fluorescent amyloid markers,
LCOs, reporting on separate ultrastructural elements, we show that
conformational rearrangement occurs within Aβ plaques of transgenic
mouse models as the animals age. This important mechanistic insight
should aid the design and evaluation of experiments currently using
plaque load as readout
Evidence for Age-Dependent <i>in Vivo</i> Conformational Rearrangement within Aβ Amyloid Deposits
Deposition
of aggregated Aβ peptide in the brain is one of the major hallmarks
of Alzheimer’s disease. Using a combination of two structurally
different, but related, hypersensitive fluorescent amyloid markers,
LCOs, reporting on separate ultrastructural elements, we show that
conformational rearrangement occurs within Aβ plaques of transgenic
mouse models as the animals age. This important mechanistic insight
should aid the design and evaluation of experiments currently using
plaque load as readout