NMDA receptor/amyloid precursor protein interactions: A comparison between wild-type and amyloid precursor protein mutations associated with familial Alzheimer's disease

Innocent, Neal; Cousins, Sarah L.; Stephenson, F. Anne

doi:10.1016/j.neulet.2012.03.029

Cited by 14 publications

(8 citation statements)

References 23 publications

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“…APP is present presynaptically in the active zone where it has multiple potential interaction partners, including synaptic vesicle proteins, transporters and channels, and cell adhesion molecules [62]. APP is also present postsynaptically where it has been shown to coprecipitate with N-methyl-D-aspartate receptor (NMDAR) subunits [63], and may be involved in surface trafficking of NMDARs [64,65]. Thus, altered expression of APP may result in altered NMDA signaling, which is crucial for learning and memory.…”

Section: Discussionmentioning

confidence: 99%

Impairment of fragile X mental retardation protein-metabotropic glutamate receptor 5 signaling and its downstream cognates ras-related C3 botulinum toxin substrate 1, amyloid beta A4 precursor protein, striatal-enriched protein tyrosine phosphatase, and homer 1, in autism: a postmortem study in cerebellar vermis and superior frontal cortex

et al. 2013

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BackgroundCandidate genes associated with idiopathic forms of autism overlap with other disorders including fragile X syndrome. Our laboratory has previously shown reduction in fragile X mental retardation protein (FMRP) and increase in metabotropic glutamate receptor 5 (mGluR5) in cerebellar vermis and superior frontal cortex (BA9) of individuals with autism.MethodsIn the current study we have investigated expression of four targets of FMRP and mGluR5 signaling - homer 1, amyloid beta A4 precursor protein (APP), ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched protein tyrosine phosphatase (STEP) - in the cerebellar vermis and superior frontal cortex (BA9) via SDS-PAGE and western blotting. Data were analyzed based on stratification with respect to age (children and adolescents vs. adults), anatomic region of the brain (BA9 vs. cerebellar vermis), and impact of medications (children and adolescents on medications (n = 4) vs. total children and adolescents (n = 12); adults on medications (n = 6) vs. total adults (n = 12)).ResultsThere were significant increases in RAC1, APP 120 kDa and APP 80 kDa proteins in BA9 of children with autism vs. healthy controls. None of the same proteins were significantly affected in cerebellar vermis of children with autism. In BA9 of adults with autism there were significant increases in RAC1 and STEP 46 kDa and a significant decrease in homer 1 vs. controls. In the vermis of adult subjects with autism, RAC1 was significantly increased while APP 120, STEP 66 kDa, STEP 27 kDa, and homer 1 were significantly decreased when compared with healthy controls. No changes were observed in vermis of children with autism. There was a significant effect of anticonvulsant use on STEP 46 kDa/β-actin and a potential effect on homer 1/NSE, in BA9 of adults with autism. However, no other significant confound effects were observed in this study.ConclusionsOur findings provide further evidence of abnormalities in FMRP and mGluR5 signaling partners in brains of individuals with autism and open the door to potential targeted treatments which could help ameliorate the symptoms of autism.

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Section: Discussionmentioning

confidence: 99%

Impairment of fragile X mental retardation protein-metabotropic glutamate receptor 5 signaling and its downstream cognates ras-related C3 botulinum toxin substrate 1, amyloid beta A4 precursor protein, striatal-enriched protein tyrosine phosphatase, and homer 1, in autism: a postmortem study in cerebellar vermis and superior frontal cortex

et al. 2013

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“…It is involved in several physiological processes, such as neuronal growth (Young-Pearse et al, 2008; Wang S. et al, 2016), the proliferation and differentiation of neural stem cells and progenitor cells (Hu et al, 2013; Bolós et al, 2014), and synaptic plasticity. Numerous studies have reported that APP promotes the formation of dendritic spines (Lee et al, 2010), alters the expression of NMDA receptors on the cell surface (Hoe et al, 2009; Innocent et al, 2012), and regulates LTP and spatial memory (Taylor et al, 2008). However, the precise roles of APP in these processes under normal conditions remain unknown (Dawkins and Small, 2014).…”

Section: Expression Of Metzincins In Alzheimer’s Diseasementioning

confidence: 99%

Multifaceted Roles of Metzincins in CNS Physiology and Pathology: From Synaptic Plasticity and Cognition to Neurodegenerative Disorders

Brzdąk

Nowak

Wiera

et al. 2017

Front. Cell. Neurosci.

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The extracellular matrix (ECM) and membrane proteolysis play a key role in structural and functional synaptic plasticity associated with development and learning. A growing body of evidence underscores the multifaceted role of members of the metzincin superfamily, including metalloproteinases (MMPs), A Disintegrin and Metalloproteinases (ADAMs), A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTSs) and astacins in physiological and pathological processes in the central nervous system (CNS). The expression and activity of metzincins are strictly controlled at different levels (e.g., through the regulation of translation, limited activation in the extracellular space, the binding of endogenous inhibitors and interactions with other proteins). Thus, unsurprising is that the dysregulation of proteolytic activity, especially the greater expression and activation of metzincins, is associated with neurodegenerative disorders that are considered synaptopathies, especially Alzheimer’s disease (AD). We review current knowledge of the functions of metzincins in the development of AD, mainly the proteolytic processing of amyloid precursor protein, the degradation of amyloid β (Aβ) peptide and several pathways for Aβ clearance across brain barriers (i.e., blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB)) that contain specific receptors that mediate the uptake of Aβ peptide. Controlling the proteolytic activity of metzincins in Aβ-induced pathological changes in AD patients’ brains may be a promising therapeutic strategy.

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“…Overexpression of APP affects Ca v 1.2 L-type calcium channel levels and through this influence GABAergic short-term plasticity (Yang et al, 2009 ). APP may contribute to postsynaptic mechanisms via the regulation of the surface trafficking of excitatory N-methyl-D-aspartate (NMDA) receptors (Innocent et al, 2012 ). Aβ was also shown binding to a number of receptors embedded in neuronal plasma membrane, (such as PrP, EphB2, FcγRIIb, and PirB), potentially contributing to receptor-mediated synaptotoxic pathways (Benilova and De Strooper, 2013 ).…”

Section: Beyond Alzheimer's: Multiple Roles Of App Potentially Affectmentioning

confidence: 99%

Inter-Dependent Mechanisms Behind Cognitive Dysfunction, Vascular Biology and Alzheimer's Dementia in Down Syndrome: Multi-Faceted Roles of APP

Nižetić

Chen

Hong

et al. 2015

Front. Behav. Neurosci.

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People with Down syndrome (DS) virtually all develop intellectual disability (ID) of varying degree of severity, and also have a high risk of early Alzheimer's disease (AD). ID prior to the onset of dementia, and its relationship to the onset of dementia in DS is a complex phenomenon influenced by many factors, and scarcely understood. Unraveling the causative factors and modulators of these processes remains a challenge, with potential to be informative for both ID and AD, for the development of early biomarkers and/or therapeutic approaches. We review the potential relative and inter-connected roles of the chromosome 21 gene for amyloid precursor protein (APP), in both pathological conditions. Rare non-DS people with duplication of APP (dupAPP) get familial early onset AD (FEOAD) with virtually 100% penetrance and prominent cerebrovascular pathology, but don't suffer from ID before dementia onset. All of these features appear to be radically different in DS. On the other hand, rare individuals with partial trisomy 21 (T21) (with APP, but not DS-critical region in trisomy) have been described having ID. Likewise, partial T21 DS (without APP trisomy) show a range of ID, but no AD pathology. We review the multi-faceted roles of APP that might affect cognitive functioning. Given the fact that both Aβ secretion and synaptic maturation/plasticity are dependent on neuronal activity, we explore how this conflicting inter-dependency might affect cognitive pathogenesis in a dynamic way in DS, throughout the lifespan of an individual.

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NMDA receptor/amyloid precursor protein interactions: A comparison between wild-type and amyloid precursor protein mutations associated with familial Alzheimer's disease

Cited by 14 publications

References 23 publications

Multifaceted Roles of Metzincins in CNS Physiology and Pathology: From Synaptic Plasticity and Cognition to Neurodegenerative Disorders

Inter-Dependent Mechanisms Behind Cognitive Dysfunction, Vascular Biology and Alzheimer's Dementia in Down Syndrome: Multi-Faceted Roles of APP

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