The role of synaptic activity in the regulation of amyloid beta levels in Alzheimer's disease

Cheng, Xiaofang; Wu, Jian Nan; Geng, Miao; Xiong, Jiaxiang

doi:10.1016/j.neurobiolaging.2013.11.021

Cited by 42 publications

(42 citation statements)

References 213 publications

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“…Generally, changes in spine shape, -size and number depend on local cytoskeletal dynamics and signalling with synaptic activity being one of the most important factors that regulate Aβ levels [6]. …”

Section: Discussionmentioning

confidence: 99%

“…Generally, synaptic activity is one of the most important factors that regulate Aβ levels [6] and involves signalling mechanisms that shape signalling pathways of long-term potentiation (LTP) and –depression (LTD); modulation of these have been summarized as synaptic plasticity. While LTP is, in part, due to activation of protein kinases, such as calmodulin-kinases (Camk's), protein kinases-A (PKA`s) and -C (PKC`s), phosphorylating downstream target proteins, LTD arises from activation of calcium-dependent phosphatases such as types 1 (PP1) and 2 (PP2) dephosphorylating proteins [7].…”

Section: Introductionmentioning

confidence: 99%

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An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

et al. 2016

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The aim of this study was to elucidate the molecular signature of Alzheimer's disease-associated amyloid pathology.We used the double APPswe/PS1ΔE9 mouse, a widely used model of cerebral amyloidosis, to compare changes in proteome, including global phosphorylation and sialylated N-linked glycosylation patterns, pathway-focused transcriptome and neurological disease-associated miRNAome with age-matched controls in neocortex, hippocampus, olfactory bulb and brainstem. We report that signalling pathways related to synaptic functions associated with dendritic spine morphology, neurite outgrowth, long-term potentiation, CREB signalling and cytoskeletal dynamics were altered in 12 month old APPswe/PS1ΔE9 mice, particularly in the neocortex and olfactory bulb. This was associated with cerebral amyloidosis as well as formation of argyrophilic tangle-like structures and microglial clustering in all brain regions, except for brainstem. These responses may be epigenetically modulated by the interaction with a number of miRNAs regulating spine restructuring, Aβ expression and neuroinflammation.We suggest that these changes could be associated with development of cognitive dysfunction in early disease states in patients with Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

et al. 2016

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“…In the systems model, the APP production was approximated to follow zero-order kinetics. In reality, APP production is regulated by various factors (above all, the synaptic activity) (Cheng et al, 2014). In this analysis, no quantitative data on the factors involved in APP production were available.…”

Section: Systems Pharmacology Analysis Of the Amyloid Cascade Discussionmentioning

confidence: 99%

Systems Pharmacology Analysis of the Amyloid Cascade after -Secretase Inhibition Enables the Identification of an A 42 Oligomer Pool

Maanen

Steeg

Michener

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The deposition of amyloid-b (Ab) oligomers in brain parenchyma has been implicated in the pathophysiology of Alzheimer's disease. Here we present a systems pharmacology model describing the changes in the amyloid precursor protein (APP) pathway after administration of three different doses (10, 30, and 125 mg/kg) of the b-secretase 1 (BACE1) inhibitor MBi-5 in cisterna magna ported rhesus monkeys. The time course of the MBi-5 concentration in plasma and cerebrospinal fluid (CSF) was analyzed in conjunction with the effect on the concentrations of the APP metabolites Ab42, Ab40, soluble b-amyloid precursor protein (sAPP) a, and sAPPb in CSF. The systems pharmacology model contained expressions to describe the production, elimination, and brain-to-CSF transport for the APP metabolites.Upon administration of MBi-5, a dose-dependent increase of the metabolite sAPPa and dose-dependent decreases of sAPPb and Ab were observed. Maximal inhibition of BACE1 was close to 100% and the IC 50 value was 0.0256 mM (95% confidence interval, 0.0137-0.0375). A differential effect of BACE1 inhibition on Ab40 and Ab42 was observed, with the Ab40 response being larger than the Ab42 response. This enabled the identification of an Ab42 oligomer pool in the systems pharmacology model. These findings indicate that decreases in monomeric Ab responses resulting from BACE1 inhibition are partially compensated by dissociation of Ab oligomers and suggest that BACE1 inhibition may also reduce the putatively neurotoxic oligomer pool.

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“…Recent studies indicate that synaptic activity regulates Aβ levels in AD, which are primarily associated with the regulation of APP endocytosis and cleavage. Glutamatergic, cholinergic, serotonergic, leptin, adrenergic, orexin, and gamma-amino butyric acid receptors, as well as the activity-regulated cytoskeleton-associated protein are all involved in these processes (21). Aβ exists in numerous accumulation forms, including Aβ monomer, Aβ oligomers and Aβ fibrils.…”

Section: Association Between Synaptic Plasticity and Aβmentioning

confidence: 99%

Role of amyloid β protein receptors in mediating synaptic plasticity

et al. 2017

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Abstract. There are few diseases in modern biomedicine that have garnered as much scientific interest and public concern as Alzheimer's disease (AD). The amyloid hypothesis has become the dominant model of AD pathogenesis; however, the details of the hypothesis are changing over time. Recently, given the increasing recognition, subtle effects of amyloid β protein (Aβ) on synaptic efficacy may be critical to AD progression. Synaptic plasticity is the important neurochemical foundation of learning and memory. Recent studies have identified that soluble Aβ oligomers combine with certain receptors to impair synaptic plasticity in AD, which advanced the amyloid hypothesis. The aim of the present review was to summarize the role of Aβ-relevant receptors in regulating synaptic plasticity and their downstream signaling cascades, which may provide novel insights into the understanding of the pathogenesis of AD and the development of therapeutic strategies to slow down the progression of AD-associated memory decline in the early stages.

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The role of synaptic activity in the regulation of amyloid beta levels in Alzheimer's disease

Cited by 42 publications

References 213 publications

An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

An integrated proteomics approach shows synaptic plasticity changes in an APP/PS1 Alzheimer's mouse model

Systems Pharmacology Analysis of the Amyloid Cascade after -Secretase Inhibition Enables the Identification of an A 42 Oligomer Pool

Role of amyloid β protein receptors in mediating synaptic plasticity

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