Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models

Kostylev, Mikhail A.; Kaufman, A; Nygaard, Haakon B.; Patel, Pujan; Haas, Laura T.; Gunther, Erik C.; Vortmeyer, Alexander O.; Strittmatter, Stephen M.

doi:10.1074/jbc.m115.643577

Cited by 116 publications

(141 citation statements)

References 88 publications

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“…To investigate whether the SAM could ameliorate behavioral deficits of aged APP/PS1 transgenic mice (Jankowsky et al, 2003, 2004), we assessed their behavior in multiple behavioral paradigms after 4 weeks of treatment with the SAM or vehicle. Because this mouse strain develops behavioral deficits starting at 6 months of age, when Aβo levels rise (Gimbel et al, 2010; Kostylev et al, 2015; Park et al, 2006), their deficits were well-established when SAM treatment started at an average age of 14 months (Figure S2). First, mice were subjected to novel object recognition testing (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes

et al. 2017

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SUMMARY Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer’s disease (AD) pathology. We sought to understand whether mGluR5’s role in AD requires glutamate signaling. We used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to separate its well-known physiological role in glutamate signaling from a pathological role in mediating amyloid-β oligomer (Aβo) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrPC) bound to Aβo. The SAM compound prevents Aβo-induced signal transduction in brain slices and in an AD transgenic mouse model, the APPswe/PS1 ΔE9 strain. Critically, 4 weeks of SAM treatment rescues memory deficits and synaptic depletion in the APPswe/PS1ΔE9 transgenic mouse brain. Our data show that mGluR5’s role in Aβo-dependent AD phenotypes is separate from its role in glutamate signaling, and silent allosteric modulation of mGluR5 has promise as a disease-modifying AD intervention with a broad therapeutic window.

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Section: Resultsmentioning

confidence: 99%

Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes

et al. 2017

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“…Kostylev and colleagues used a PrP C -ELISA (PLISA) to quantify the Aβo-PrP C interaction in brain tissue from several mouse models of AD and also healthy and AD human brain [9, 21]. This study found that PrP C interacting Aβo are highly correlated with learning and memory deficits in multiple mouse models of AD as defined by PLISA activity [21]. Furthermore, PLISA activity disappeared with PrP C mediated depletion of high-molecular weight Aβo from mouse of the varying mouse models.…”

Section: Cellular Prion Protein (Prpc) As a Receptor For Aβomentioning

confidence: 99%

Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease

Salazar

Strittmatter

2017

Biochemical and Biophysical Research Communications

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Soluble oligomers of amyloid-beta (Aβo) are implicated by biochemical and genetic evidence as a trigger for Alzheimer’s disease (AD) pathophysiology. A key step is Aβo interaction with the neuronal surface to initiate a cascade of altered signal transduction leading to synaptic dysfunction and damage. This review discusses neuronal cell surface molecules with high affinity selectively for oligomeric disease-associated states of Aβ, with a particular focus on the role of cellular prion protein (PrPC) in this process. Additional receptors may contribute to mediation of Aβo action, but PrPC appears to play a primary role in a number of systems. The specificity of binding, the genetic necessity in mouse models of disease and downstream signaling pathways are considered. Signal transduction downstream of Aβo complexes with PrPC involves metabotropic glutamate receptor 5 (mGluR5), Fyn kinase and Pyk2 kinase, with deleterious effects on synaptic transmission and maintenance. Current data support the hypothesis that a substantial portion of Aβo toxicity in AD is mediated after initial interaction with PrPC on the neuronal surface. As such, the interaction of Aβo with PrPC is a potential therapeutic intervention site for AD.

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“…In vitro, exposure of soluble Aβ oligomers results in rapid blockage of long-term potentiation and binding to cellular prion protein, interfering with normal synaptic function [3,13,14,15]. Moreover, soluble Aβ oligomers may cause tau hyperphosphorylation and neuronal degeneration in hippocampal neurons [12,16,17].…”

Section: Introductionmentioning

confidence: 99%

A Study of Aβ Oligomers in the Temporal Cortex and Cerebellum of Patients with Neuropathologically Confirmed Alzheimer's Disease Compared to Aged Controls

et al. 2016

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Background/Aims: Investigations of Aβ oligomers in neuropathologically confirmed Alzheimer's disease (AD) are still scarce. We report neurohistopathological and biochemical analyses using antibodies against tau and amyloid β (Aβ) pathology. Methods: Thirty elderly AD patients and 43 age-matched controls with or without deposition of amyloid plaques (AP) were analyzed by immunohistochemistry. In 21 cases with available fresh tissue, Western blots were also performed. Neuropathological analysis included quantitative assessment of neurofibrillary tangles (NFT), AP and Aβ oligomer densities in the mesial temporal cortex (TC). Results: NFT, fibrillar amyloid and Aβ oligomeric deposit densities were significantly higher in AD patients than in controls. There was no relationship between oligomeric Aβ densities and Braak NFT staging scores. Furthermore, Aβ oligomer expression was closely correlated with Aβ plaques in the TC. By Western blot, Aβ oligomers were observed in AD patients, in plaque-free controls, in 1 ‘tangle-only AD' case, as well as in the cerebellum. A band near 55 kDa was the only Western blot signal that was significantly increased in the TC of AD patients compared to controls as well as less expressed in the cerebellum. Conclusion: These results suggest that a putative dodecamer, near 55 kDa, may contribute to AD vulnerability of the TC.

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Prion-Protein-interacting Amyloid-β Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models

Cited by 116 publications

References 88 publications

Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes

Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer’s Mouse Phenotypes

Cellular prion protein as a receptor for amyloid-β oligomers in Alzheimer's disease

A Study of Aβ Oligomers in the Temporal Cortex and Cerebellum of Patients with Neuropathologically Confirmed Alzheimer's Disease Compared to Aged Controls

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