Fragile X and APP: a Decade in Review, a Vision for the Future

Westmark, Cara J.

doi:10.1007/s12035-018-1344-x

Cited by 29 publications

(13 citation statements)

References 128 publications

(250 reference statements)

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“…Similar to the ability of inhibiting mGluR5 activity to reverse oAβ-induced memory deficits, several aberrant phenotypes of fragile X model mice are reversible by the same means (see Erickson et al, 2017;Santos et al, 2014). mGluR5, FMRP and APP processing are interconnected (Westmark, 2019): mGluR5 increases APP translation by releasing FMRP repression of APP mRNA (Westmark and Malter, 2007). Activation of mGluR5 also increases Arc (Wilkerson et al, 2018), which may promote co-localization of APP and PSEN1 in endocytic vesicles leading to increased Aβ production (Wu et al, 2011).…”

Section: The Prpc-mglur5 Complex As a Mediator Of Aβ Write-protectionmentioning

confidence: 96%

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

Murphy¹

2021

Preprint

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Alzheimer’s Disease is defined as progressive memory loss coincident with accumulation of aggregated amyloid beta and phosphorylated tau. Identifying the relationship between these features has guided Alzheimer’s Disease research for decades, principally with the view that aggregated proteins drive a neurodegenerative process. Here I propose that amyloid beta and phospho-tau write-protect and tag neuroplastic changes as they form, protecting and insuring established neuroplasticity from corruption. In way of illustration, binding of oligomeric amyloid beta to the prion receptor is presented as an example possible mechanism. The write-protecting process is conjected to occur at least partially under the governance of isodendritic neuromodulators such as norepinephrine and acetylcholine. Coincident with aging, animals are exposed to accumulating amounts of memorable information. Compounded with recent increases in life expectancy and exposure to information-rich environments this causes aggregating proteins to reach unforeseen toxic levels as mnemonic circuits overload. As the brain cannot purposefully delete memories nor protect against overaccumulation of aggregating proteins, the result is catastrophic breakdown on cellular and network levels causing memory loss.

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Section: The Prpc-mglur5 Complex As a Mediator Of Aβ Write-protectionmentioning

confidence: 96%

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

Murphy¹

2021

Preprint

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“…APP es procesada por secretasas que producen β amiloide (Aβ), péptido predominante en las placas seniles en la enfermedad de Alzheimer. 12…”

Section: Bases Biológicas Del Síndrome X Frágilunclassified

Síndrome X frágil: presentación clínica, patología y tratamiento

Salcedo-Arellano

Hagerman

Martínez‐Cerdeño

2019

GMM

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El síndrome X frágil es la condición monogenética que produce más casos de autismo y de discapacidad intelectual. La repetición de tripletes CGG (> 200) y su metilación conllevan el silenciamiento del gen FMR1. La proteína FMRP (producto del gen FMR1) interacciona con los ribosomas, controlando la traducción de mensajeros específicos y su pérdida produce alteraciones de la conectividad sináptica. El tamizaje de síndrome X frágil se realiza por reacción en cadena de la polimerasa. La recomendación actual de la Academia Americana de Pediatría es realizar pruebas a quienes presenten discapacidad intelectual, retraso global del desarrollo o antecedentes familiares de afección por la mutación o premutación. Países hispanos como Colombia, Chile y España reportan altas prevalencias de síndrome X frágil y han creado asociaciones o corporaciones nacionales de X frágil que buscan acercar a los pacientes a redes disponibles de diagnóstico y tratamiento.

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“…Furthermore, drugs that inhibit metabotropic glutamate receptor 5 (mGluR 5 ), which signals upstream of FMRP, reduce dendritic overexpression of APP in Fmr1 KO primary cultured neurons (Westmark et al, 2018) and seizures in mouse models that over-express human APP and amyloid-beta (Aβ; Westmark et al, 2009Westmark et al, , 2010. Thus, APP is both a potential therapeutic target as well as a disease biomarker for FXS (Westmark, 2019). Glycogen synthase kinase 3 (GSK3) signals downstream of mGluR 5 and upstream of FMRP, and its activation affects all major hallmarks of Alzheimer's disease and FXS (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Testing Fmr1KO Phenotypes in Response to GSK3 Inhibitors: SB216763 versus AFC03127

Westmark

Garrone

Ombrato

et al. 2021

Front. Mol. Neurosci.

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Glycogen synthase kinase 3 (GSK3) is a proline-directed serine-threonine kinase that is associated with several neurological disorders, including Alzheimer’s disease and fragile X syndrome (FXS). We tested the efficacy of a novel GSK3 inhibitor AFC03127, which was developed by Angelini Pharma, in comparison to the metabotropic glutamate receptor 5 inhibitor 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and the GSK3 inhibitor SB216763 in in vivo and in vitro assays in Fmr1KO mice, a mouse model useful for the study of FXS. The in vivo assay tested susceptibility to audiogenic-induced seizures (AGS) whereas the in vitro assays assessed biomarker expression and dendritic spine length and density in cultured primary neurons as a function of drug dose. MPEP and SB216763 attenuated AGS in Fmr1KO mice, whereas AFC03127 did not. MPEP and AFC03127 significantly reduced dendritic expression of amyloid-beta protein precursor (APP). All drugs rescued spine length and the ratio of mature dendritic spines. Spine density was not statistically different between vehicle and GSK3 inhibitor-treated cells. The drugs were tested over a wide concentration range in the in vitro assays to determine dose responses. A bell-shaped dose response decrease in APP expression was observed in response to AFC03127, which was more effective than SB216763. These findings confirm previous studies demonstrating differential effects of various GSK3 inhibitors on AGS propensity in Fmr1KO mice and confirm APP as a downstream biomarker that is responsive to GSK3 activity.

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Fragile X and APP: a Decade in Review, a Vision for the Future

Cited by 29 publications

References 128 publications

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

Alzheimer’s disease as a syndrome of overloaded amyloidic synaptic tagging in memory networks

Síndrome X frágil: presentación clínica, patología y tratamiento

Testing Fmr1KO Phenotypes in Response to GSK3 Inhibitors: SB216763 versus AFC03127

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