Genetic Modulation of Soluble A  Rescues Cognitive and Synaptic Impairment in a Mouse Model of Alzheimer's Disease

Fowler, Stephanie; Chiang, Angie C.A.; Savjani, Ricky R.; Larson, Megan; Sherman, Mathew A.; Schuler, Dorothy R.; Cirrito, John R.; Lesné, Sylvain; Jankowsky, Joanna L.

doi:10.1523/jneurosci.0572-14.2014

Cited by 76 publications

(70 citation statements)

References 71 publications

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“…This is in agreement with the correlation of soluble A␤ and oA␤ with cognitive decline and disease severity in humans (70), and the association of oA␤ levels with memory decline in FAD-Tg mice (70). Furthermore, recent data demonstrate that transient soluble oA␤ levels may underlie neuronal deficits in FAD-Tg mice using a genetic approach (71). However, as a dynamic equilibrium likely exists between soluble and insoluble A␤ levels (i.e.…”

Section: E4fad-hpsupporting

confidence: 84%

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

Tai

Koster

Luo

et al. 2014

Journal of Biological Chemistry

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Background: Human APOE effects on RXR agonist activity are unclear. Results: In RXR agonist-treated EFAD mice, beneficial effects in APOE4 hippocampus include ABCA1/ABCG1-induced apoE lipoprotein association/lipidation. Detrimental effects in APOE3 and APOE4 cortex might be from systemic hepatomegaly. Conclusion: A␤ pathology and APOE genotype modulate RXR agonist effects. Significance: Although promising for later stage Alzheimer disease, detrimental side effects limit translational application of RXR agonists.

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Section: E4fad-hpsupporting

confidence: 84%

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

Tai

Koster

Luo

et al. 2014

Journal of Biological Chemistry

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“…A recent study using a TET-off APP overexpressing mouse model observed cognitive improvement in the absence of changes in amyloid plaques when the transgenic APP gene was turned off [74]. This finding supports the hypothesis that blocking the binding and effects of Abeta oligomers can have a therapeutic effect in the absence of plaque clearance.…”

Section: Discussionsupporting

confidence: 69%

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors Is Displaced by Drug Candidates That Improve Cognitive Deficits

et al. 2014

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Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1–42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors - i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics.

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“…Consistent with the effect of Aβ in vitro, we found that C3 mRNA levels were significantly higher in APP/TTA double transgenic mice than in TTA single-transgenic controls (Figure 7D) (Jankowsky et al, 2005). We then treated mice with C3aRA or vehicle DMSO for 3 weeks before testing their performance in Morris water maze (MWM) and radial arm water maze (RAWM) (Fowler et al, 2014). Treatment was initiated at an age when cognitive impairments are already manifested, and consistent with past characterization of this model, vehicle-treated APP/TTA mice took more days of training than TTA controls to reach criteria performance in the MWM and made more working memory errors in the RAWM (Figures 7E and 7F).…”

Section: Resultsmentioning

confidence: 99%

NFκB-Activated Astroglial Release of Complement C3 Compromises Neuronal Morphology and Function Associated with Alzheimer’s Disease

Lian¹,

Yang²,

Cole³

et al. 2015

Neuron

537

440

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SUMMARY Abnormal NFκB activation has been implicated in Alzheimer’s disease (AD). However, the signaling pathways governing NFκB regulation and function in the brain are poorly understood. We identify complement protein C3 as an astroglial target of NFκB, and show that C3 release acts through neuronal C3aR to disrupt dendritic morphology and network function. Exposure to Aβ activates astroglial NFκB and C3 release, consistent with the high levels of C3 expression in brain tissue from AD patients and APP transgenic mice, where C3aR antagonist treatment rescues cognitive impairment. Thus, dysregulation of neuron-glia interaction through NFκB/C3/C3aR signaling may contribute to synaptic dysfunction in AD and C3aR antagonists may be therapeutically beneficial.

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Genetic Modulation of Soluble A Rescues Cognitive and Synaptic Impairment in a Mouse Model of Alzheimer's Disease

Cited by 76 publications

References 71 publications

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors Is Displaced by Drug Candidates That Improve Cognitive Deficits

NFκB-Activated Astroglial Release of Complement C3 Compromises Neuronal Morphology and Function Associated with Alzheimer’s Disease

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