Rescue of Transgenic Alzheimer’s Pathophysiology by Polymeric Cellular Prion Protein Antagonists

Gunther, Erik C.; Smith, Levi M.; Kostylev, Mikhail A.; Cox, Timothy; Kaufman, A; Lee, Suho; Folta‐Stogniew, Ewa; Maynard, George D.; Um, Ji Won; Stagi, Massimiliano; Heiss, Jacqueline K.; Stoner, Austin; Noble, Geoff P.; Takahashi, Hideyuki; Haas, Laura T.; Schneekloth, John S.; Merkel, Janie; Teran, Christopher A.; Naderi, Zahra K.; Supattapone, Surachai; Strittmatter, Stephen M.

doi:10.1016/j.celrep.2018.12.021

Cited by 30 publications

(15 citation statements)

References 47 publications

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“…However, the magnitude of the group difference at baseline was greatly reduced. APP/PS1 mice do have amyloid-b plaque disease in the cortex at this age (10,20), and Gimbel et al (13) showed about a 15% decrease in the frontal cortex. If there is loss of synaptic density in the cortex, then SUVR (WB) will underestimate the magnitude of between-group differences.…”

Section: Agreement With Ex Vivo and In Vivo Resultsmentioning

confidence: 91%

In Vivo Synaptic Density Imaging with ¹¹C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease

et al. 2019

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11 C-UCB-J is a new PET tracer for synaptic density imaging. Recently, we conducted 11 C-UCB-J PET on patients with mild cognitive impairment or early Alzheimer disease (AD) and found a 41% decrease in specific binding in the hippocampus compared with healthy subjects. We hypothesized that 11 C-UCB-J may have potential to be a general biomarker for evaluating AD treatment effects via monitoring of synaptic density changes. In this study, we performed longitudinal 11 C-UCB-J PET on AD mice to measure the treatment effects of saracatinib, which previously demonstrated synaptic changes with postmortem methods. Methods: Nine wildtype (WT) mice and 9 amyloid precursor protein and presenilin 1 double-transgenic (APPswe/PS1DE9 [APP/PS1]) mice underwent 3 11 C-UCB-J PET measurements: at baseline, after treatment, and during drug washout. After baseline measurements, saracatinib, a Fyn kinase inhibitor currently in clinical development for AD treatment, was administered by oral gavage for 41 ± 11 d. Treatmentphase measurements were performed on the last day of treatment, and washout-phase measurements occurred more than 27 d after the end of treatment. SUVs from 30 to 60 min after injection of 11 C-UCB-J were calculated and normalized by the whole-brain (WB) or brain stem (BS) average values as SUV ratio (SUVR (WB) or SUVR-1 (BS)). Results: Hippocampal SUVR (WB) at baseline was significantly lower in APP/PS1 than WT mice (APP/PS1: 1.11 ± 0.04, WT: 1.15 ± 0.02, P 5 0.033, unpaired t test). Using SUVR-1 (BS) in the hippocampus, there was also a significant difference at baseline (APP/ PS1: 0.48 ± 0.13, WT: 0.65 ± 0.10, P 5 0.017, unpaired t test). After treatment with saracatinib, hippocampal SUVR (WB) in APP/PS1 mice was significantly increased (P 5 0.037, paired t test). A trend-level treatment effect was seen with hippocampal SUVR-1 (BS). Saracatinib treatment effects may persist, as there were no significant differences between WT and APP/PS1 mice after drug washout. Conclusion: On the basis of the 11 C-UCB-J PET results, hippocampal synaptic density was lower in APP/PS1 mice than in WT mice at baseline, and this deficit was normalized by treatment with saracatinib. These results support the use of 11 C-UCB-J PET to identify disease-specific synaptic deficits and to monitor treatment effects in AD.

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Section: Agreement With Ex Vivo and In Vivo Resultsmentioning

confidence: 91%

In Vivo Synaptic Density Imaging with ¹¹C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease

et al. 2019

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“…Certain metallated porphyrins 36,37 interact with PrP with affinity values comparable to their effective concentrations in cell culture 36,37 , and some exhibit in vivo activity in certain paradigms 38 . Similarly, a range of anionic polymers 33,[39][40][41][42] also bind PrP and show in vivo antiprion activity in certain contexts 41,43,44 . However, these binding events may not be monomeric 45 nor specific to PrP 35,46 .…”

Section: Decades Of Effortmentioning

confidence: 99%

Multimodal small-molecule screening for human prion protein binders

Reidenbach

Mesleh

Casalena³

et al. 2020

Journal of Biological Chemistry

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Prion disease is a rapidly progressive neurodegenerative disorder caused by misfolding and aggregation of the prion protein (PrP), and there are currently no therapeutic options. PrP ligands could theoretically antagonize prion formation by protecting the native protein from misfolding or by targeting it for degradation, but no validated small-molecule binders have been discovered to date. We deployed a variety of screening methods in an effort to discover binders of PrP, including 19F-observed and saturation transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, differential scanning fluorimetry (DSF), DNA-encoded library selection, and in silico screening. A single benzimidazole compound was confirmed in concentration-response, but affinity was very weak (Kd > 1 mM), and it could not be advanced further. The exceptionally low hit rate observed here suggests that PrP is a difficult target for small-molecule binders. While orthogonal binder discovery methods could yield high affinity compounds, non-small-molecule modalities may offer independent paths forward against prion disease.

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“…In vivo, genetic deletion of PrP C rescues behavioral deficits, synaptic loss, and early mortality in AD transgenic models 29 , 30 . Compounds that block Aβ binding to PrP C , or that inhibit activation of downstream signaling mechanisms, have been shown to ameliorate pathology in AD transgenic models 31 , 32 , and some of these are being tested in human patients 33 .…”

Section: Introductionmentioning

confidence: 99%

Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers

Amin

2021

Nat Commun

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Several cell-surface receptors for neurotoxic forms of amyloid-β (Aβ) have been described, but their molecular interactions with Aβ assemblies and their relative contributions to mediating Alzheimer’s disease pathology have remained uncertain. Here, we used super-resolution microscopy to directly visualize Aβ-receptor interactions at the nanometer scale. We report that one documented Aβ receptor, PrPC, specifically inhibits the polymerization of Aβ fibrils by binding to the rapidly growing end of each fibril, thereby blocking polarized elongation at that end. PrPC binds neurotoxic oligomers and protofibrils in a similar fashion, suggesting that it may recognize a common, end-specific, structural motif on all of these assemblies. Finally, two other Aβ receptors, FcγRIIb and LilrB2, affect Aβ fibril growth in a manner similar to PrPC. Our results suggest that receptors may trap Aβ oligomers and protofibrils on the neuronal surface by binding to a common molecular determinant on these assemblies, thereby initiating a neurotoxic signal.

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Rescue of Transgenic Alzheimer’s Pathophysiology by Polymeric Cellular Prion Protein Antagonists

Cited by 30 publications

References 47 publications

In Vivo Synaptic Density Imaging with ¹¹C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease

In Vivo Synaptic Density Imaging with ¹¹C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease

Multimodal small-molecule screening for human prion protein binders

Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers

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Rescue of Transgenic Alzheimer’s Pathophysiology by Polymeric Cellular Prion Protein Antagonists

Cited by 30 publications

References 47 publications

In Vivo Synaptic Density Imaging with 11C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease

In Vivo Synaptic Density Imaging with 11C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease

Multimodal small-molecule screening for human prion protein binders

Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers

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Product

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In Vivo Synaptic Density Imaging with ¹¹C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease

In Vivo Synaptic Density Imaging with ¹¹C-UCB-J Detects Treatment Effects of Saracatinib in a Mouse Model of Alzheimer Disease