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Pyroglutamate-3 amyloid-? deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models.

ABSTRACT: Amyloid-? (A?) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 A?), are a major species deposited in the brain of Alzheimer disease (AD) patients. Recent studies suggest that this isoform shows higher toxicity and amyloidogenecity when compared to full-length A? peptides. Here, we report the first comprehensive and comparative IHC evaluation of pyroGlu-3 A? deposition in humans and animal models. PyroGlu-3 A? immunoreactivity (IR) is abundant in plaques and cerebral amyloid angiopathy of AD and Down syndrome patients, colocalizing with general A? IR. PyroGlu-3 A? is further present in two nontransgenic mammalian models of cerebral amyloidosis, Caribbean vervets, and beagle canines. In addition, pyroGlu-3 A? deposition was analyzed in 12 different AD-like transgenic mouse models. In contrast to humans, all transgenic models showed general A? deposition preceding pyroGlu-3 A? deposition. The findings varied greatly among the mouse models concerning age of onset and cortical brain region. In summary, pyroGlu-3 A? is a major species of ?-amyloid deposited early in diffuse and focal plaques and cerebral amyloid angiopathy in humans and nonhuman primates, whereas it is deposited later in a subset of focal and vascular amyloid in AD-like transgenic mouse models. Given the proposed decisive role of pyroGlu-3 A? peptides for the development of human AD pathology, this study provides insights into the usage of animal models in AD studies.

SUBMITTER: Frost JL

PROVIDER: S-EPMC3730768 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Pyroglutamate-3 amyloid-β deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models.

Frost Jeffrey L JL Le Kevin X KX Cynis Holger H Ekpo Elizabeth E Kleinschmidt Martin M Palmour Roberta M RM Ervin Frank R FR Snigdha Shikha S Cotman Carl W CW Saido Takaomi C TC Vassar Robert J RJ St George-Hyslop Peter P Ikezu Tsuneya T Schilling Stephan S Demuth Hans-Ulrich HU Lemere Cynthia A CA

The American journal of pathology 20130607 2

Amyloid-β (Aβ) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 Aβ), are a major species deposited in the brain of Alzheimer disease (AD) patients. Recent studies suggest that this isoform shows higher toxicity and amyloidogenecity when compared to full-length Aβ peptides. Here, we report the first comprehensive and comparative IHC evaluation of pyroGlu-3 Aβ deposition in humans and animal models. PyroGlu-3 Aβ immunoreactivity (IR) is abundant in plaques and cerebral amyloid ...[more]

PMID: 23747948

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Project description:PurposePathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (A?) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and A? deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis.MethodsPET imaging with the amyloid plaque tracer (11)C-AZD2184 and the astroglial tracer (11)C-deuterium-L-deprenyl ((11)C-DED) was carried out in APPswe mice aged 6, 8-15 and 18-24 months (4-6 animals/group) and in wild-type (wt) mice aged 8-15 and 18-24 months (3-6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for A? deposition and astrocytosis by in vitro autoradiography using (3)H-AZD2184, (3)H-Pittsburgh compound B (PIB) and (3)H-L-deprenyl and immunostaining performed with antibodies for A?42 and glial fibrillary acidic protein (GFAP) in sagittal brain sections.Results(11)C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18-24 months than in age-matched wt mice. Cortical and hippocampal (11)C-DED PET binding was significantly higher at 6 months than at 8-15 months or 18-24 months in APPswe mice, and it was also higher than at 8-15 months in wt mice. In vitro autoradiography (3)H-AZD2184 and (3)H-PIB binding confirmed the in vivo findings with (11)C-AZD2184 and demonstrated age-dependent increases in A? deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in (3)H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more A?42 deposits in the cortex and hippocampus and more GFAP(+) reactive astrocytes in the hippocampus at 18-24 months than at 6 months in APPswe mice.ConclusionThe findings provide further in vivo evidence that astrocytosis occurs early in AD, preceding A? plaque deposition.

Project description:BackgroundAggregated amyloid-β (Aβ) is considered a pathogenic initiator of Alzheimer's disease (AD), in strong association with tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and cognitive decline. As the removal of amyloid burden from AD patient brains by antibodies has shown therapeutic potential, the development of small molecule drugs inducing chemical dissociation and clearance of Aβ is compelling as a therapeutic strategy. In this study, we synthesized and screened aryloxypropanolamine derivatives and identified 1-(3-(2,4-di-tert-pentylphenoxy)-2-hydroxypropyl)pyrrolidin-1-ium chloride, YIAD002, as a strong dissociator of Aβ aggregates.MethodsThe dissociative activity of aryloxypropanolamine derivatives against Aβ aggregates were evaluated through in vitro assays. Immunohistochemical staining, immunoblot assays, and the Morris water maze were used to assess the anti-Alzheimer potential in YIAD002-treated 5XFAD and transgenic APP/PS1 mice. Target-ligand interaction mechanism was characterized via a combination of peptide mapping, fluorescence dissociation assays, and constrained docking simulations.ResultsAmong 11 aryloxypropanolamine derivatives, YIAD002 exerted strongest dissociative activity against β-sheet-rich Aβ aggregates. Upon oral administration, YIAD002 substantially reduced amyloid burden and accordingly, improved cognitive performance in the Morris water maze and attenuated major pathological hallmarks of AD including tauopathy, neuroinflammation, and synaptic protein loss. Mechanism studies suggest that YIAD002 interferes with intermolecular β-sheet fibrillation by directly interacting with KLVFFA and IGLMVG domains of Aβ. In addition, YIAD002 was found to possess dissociative activity against aggregates of pyroglutamate-modified Aβ and tau.ConclusionsCollectively, our results evince the potential of chemical-driven dissociation of Aβ aggregates by aryloxypropanolamines as a therapeutic modality of the amyloid clearance approach.

Dataset Information

Pyroglutamate-3 amyloid-? deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models.

Publications

Pyroglutamate-3 amyloid-β deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models.

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