4 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
Divergent Age-Dependent Conformational Rearrangement within Aβ Amyloid Deposits in APP23, APPPS1, and <i>App</i><sup><i>NL‑F</i></sup> Mice
Amyloid plaques composed of fibrils of misfolded Aβ
peptides
are pathological hallmarks of Alzheimer’s disease (AD). Aβ
fibrils are polymorphic in their tertiary and quaternary molecular
structures. This structural polymorphism may carry different pathologic
potencies and can putatively contribute to clinical phenotypes of
AD. Therefore, mapping of structural polymorphism of Aβ fibrils
and structural evolution over time is valuable to understanding disease
mechanisms. Here, we investigated how Aβ fibril structures in
situ differ in Aβ plaque of different mouse models expressing
familial mutations in the AβPP gene. We imaged frozen brains
with a combination of conformation-sensitive luminescent conjugated
oligothiophene (LCO) ligands and Aβ-specific antibodies. LCO
fluorescence mapping revealed that mouse models APP23, APPPS1, and AppNL‑F have different
fibril structures within Aβ-amyloid plaques depending on the
AβPP-processing genotype. Co-staining with Aβ-specific
antibodies showed that individual plaques from APP23 mice expressing
AβPP Swedish mutation have two distinct fibril polymorph regions
of core and corona. The plaque core is predominantly composed of compact
Aβ40 fibrils, and the corona region is dominated by diffusely
packed Aβ40 fibrils. Conversely, the AβPP knock-in mouse AppNL‑F, expressing the
AβPP Iberian mutation along with Swedish mutation has tiny,
cored plaques consisting mainly of compact Aβ42 fibrils, vastly
different from APP23 even at elevated age up to 21 months. Age-dependent
polymorph rearrangement of plaque cores observed for APP23 and APPPS1
mice >12 months, appears strongly promoted by Aβ40 and was
hence
minuscule in AppNL‑F. These structural studies of amyloid plaques in situ can map
disease-relevant fibril polymorph distributions to guide the design
of diagnostic and therapeutic molecules
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