Whole‐brain microscopy reveals distinct temporal and spatial efficacy of anti‐Aβ therapies

Kirschenbaum, Daniel S.; Dadgar‐Kiani, Ehsan; Catto, Francesca; Voigt, Fabian F.; Trevisan, Chiara; Bichsel, Oliver; Shirani, Hamid; Nilsson, K. Peter R.; Frontzek, Karl; Paganetti, Paolo; Helmchen, Fritjof; Lee, Jin Hyung; Aguzzi, Adriano

doi:10.15252/emmm.202216789

Cited by 11 publications

(9 citation statements)

References 53 publications

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“…The regional and temporal heterogeneity of amyloid-β (Aβ) plaque formation in mouse brains subject to various treatments is a promising direction in Alzheimer’s disease research 13 . An APP/PS1 mouse brain cleared with iDISCO 47 is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Benchtop mesoSPIM: a next-generation open-source light-sheet microscope for cleared samples

Vladimirov,

Voigt,

Naert

et al. 2024

Nat Commun

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In 2015, we launched the mesoSPIM initiative, an open-source project for making light-sheet microscopy of large cleared tissues more accessible. Meanwhile, the demand for imaging larger samples at higher speed and resolution has increased, requiring major improvements in the capabilities of such microscopes. Here, we introduce the next-generation mesoSPIM (“Benchtop”) with a significantly increased field of view, improved resolution, higher throughput, more affordable cost, and simpler assembly compared to the original version. We develop an optical method for testing detection objectives that enables us to select objectives optimal for light-sheet imaging with large-sensor cameras. The improved mesoSPIM achieves high spatial resolution (1.5 µm laterally, 3.3 µm axially) across the entire field of view, magnification up to 20×, and supports sample sizes ranging from sub-mm up to several centimeters while being compatible with multiple clearing techniques. The microscope serves a broad range of applications in neuroscience, developmental biology, pathology, and even physics.

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Section: Resultsmentioning

confidence: 99%

Benchtop mesoSPIM: a next-generation open-source light-sheet microscope for cleared samples

Vladimirov,

Voigt,

Naert

et al. 2024

Nat Commun

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“…However, this is not the full explanation. A previous study treating APPPS1 mice with a BACE-1 inhibitor that decreased total Aβ production and hence the number and size of Aβ-amyloid plaque in young mice, but the qFTAA/hFTAA ratio was altered by increasing in cortical regions and decreasing in thalamus, hypothalamus, and hindbrain regions (55). No difference was seen in treated versus non-treated 14 Mo old APPPS1 mice.…”

Section: Resultsmentioning

confidence: 99%

Divergent age-dependent conformational rearrangement within Aβ amyloid deposits in APP23, APPPS1, and App^NL-Fmice

Parvin,

Haglund,

Wegenast-Braun

et al. 2023

Preprint

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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 potency and can putatively contribute to clinical phenotypes of AD. Therefore, mapping of structural polymorphism of Aβ fibrils is valuable to understand disease mechanisms. Here, we investigated how Aβ fibril morphology in situ differs in Aβ plaque of different mouse models expressing familial mutations in the AβPP gene. We used a combination of conformation-sensitive luminescent conjugated oligothiophene (LCO) ligands, Aβ-specific antibodies, and different fluorescence microscopy techniques. LCO fluorescence mapping revealed that mouse models APP23, APPPS1, and AppNL-F have different fibril structures depending on AβPP-processing genotype. Co-staining of Aβ-specific antibodies showed that individual plaques from APP23 mice, expressing Swedish mutations (NL) 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. On the other hand, the APP knock-in mouse AppNL-F, expressing Iberian mutation (F) 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 maturation of plaque cores observed for APP23 and APPPS1 mice >12 months, was 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.

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“…A previous study treating APPPS1 mice with a BACE-1 inhibitor decreased total Aβ production and hence the number and size of Aβ-amyloid plaque in young mice, but the qFTAA/hFTAA ratio was altered by increasing in cortical regions and decreasing in the thalamus, hypothalamus, and hindbrain regions. 57 No difference was seen in treated versus nontreated 14-month-old APPPS1 mice. These results indicate that the issue is more complex than merely Aβ-concentration.…”

Section: How Do Aβ Plaque Structures In Mouse Models Relate To Human ...mentioning

confidence: 95%

Divergent Age-Dependent Conformational Rearrangement within Aβ Amyloid Deposits in APP23, APPPS1, and App^NL-F Mice

Parvin,

Haglund,

Wegenast-Braun

et al. 2024

ACS Chem. Neurosci.

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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 App NL-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 App NL-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 App NL-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.

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Whole‐brain microscopy reveals distinct temporal and spatial efficacy of anti‐Aβ therapies

Cited by 11 publications

References 53 publications

Benchtop mesoSPIM: a next-generation open-source light-sheet microscope for cleared samples

Benchtop mesoSPIM: a next-generation open-source light-sheet microscope for cleared samples

Divergent age-dependent conformational rearrangement within Aβ amyloid deposits in APP23, APPPS1, and App^NL-Fmice

Divergent Age-Dependent Conformational Rearrangement within Aβ Amyloid Deposits in APP23, APPPS1, and App^NL-F Mice

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Whole‐brain microscopy reveals distinct temporal and spatial efficacy of anti‐Aβ therapies

Cited by 11 publications

References 53 publications

Benchtop mesoSPIM: a next-generation open-source light-sheet microscope for cleared samples

Benchtop mesoSPIM: a next-generation open-source light-sheet microscope for cleared samples

Divergent age-dependent conformational rearrangement within Aβ amyloid deposits in APP23, APPPS1, and AppNL-Fmice

Divergent Age-Dependent Conformational Rearrangement within Aβ Amyloid Deposits in APP23, APPPS1, and AppNL-F Mice

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Divergent age-dependent conformational rearrangement within Aβ amyloid deposits in APP23, APPPS1, and App^NL-Fmice

Divergent Age-Dependent Conformational Rearrangement within Aβ Amyloid Deposits in APP23, APPPS1, and App^NL-F Mice