A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer’s brain

Li, Shaomin; Selkoe, Dennis J.

doi:10.1111/jnc.15007

Cited by 191 publications

(185 citation statements)

References 182 publications

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“…In AD, hippocampal dysfunction is produced by synaptic failure ( Li and Selkoe, 2020 ), which leads to memory deficits. Changes in AMPARs are involved in Aβ-related synaptic dysfunction and pathophysiology of AD ( reviewed by Keifer and Zheng, 2010 ; Palop and Mucke, 2010 ; Whitehead et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Shift of AMPA Receptors From Synapses to Intracellular Compartments in Alzheimer’s Disease: Immunocytochemical Analysis of the CA1 Hippocampal Region in APP/PS1 Transgenic Mouse Model

Martín-Belmonte

Aguado

Alfaro-Ruiz

et al. 2020

Front. Aging Neurosci.

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Synapse loss occurs early in Alzheimer’s disease (AD) patients and animal models. Alterations at synaptic level are a major morphological correlate of the memory deficits and related symptoms of AD. Given the predominant roles of synaptic AMPA receptors (AMPARs) in excitatory synaptic transmission in the brain, changes in their dynamic regulation are also implicated in the pathophysiology of AD. Here, we used immunolocalization techniques to analyze the expression and subcellular distribution of AMPARs in the hippocampal region of APP/PS1 mouse model of AD. Immunoblots and histoblots revealed that the total amount of AMPARs and their regional expression pattern in the hippocampus was similar in APP/PS1 mice and in age-matched wild type mice. At the ultrastructural level, two synapse populations were examined using SDS-digested freeze-fracture replica labeling in the stratum radiatum in mice: (i) on spines of CA1 pyramidal cells; and (ii) on randomly found dendritic shafts of CA1 interneurons. While 1- and 6-months-old APP/PS1 mice exhibited no change, we observed a significant reduction at 12 months in AMPAR density at synapses in both pyramidal cells and interneurons, compared to wild-type. This reduction of AMPARs in dendritic spines was accompanied by a significant increase in AMPAR subunit proteins identified in intracellular compartments. Our data demonstrate an age-dependent reduction of synaptic AMPARs in APP/PS1 mice, which may contribute to impaired learning and memory at later stages of AD.

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Section: Discussionmentioning

confidence: 99%

Age-Dependent Shift of AMPA Receptors From Synapses to Intracellular Compartments in Alzheimer’s Disease: Immunocytochemical Analysis of the CA1 Hippocampal Region in APP/PS1 Transgenic Mouse Model

Martín-Belmonte

Aguado

Alfaro-Ruiz

et al. 2020

Front. Aging Neurosci.

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“…Thus, it will be interesting to investigate whether pSer8Aβ and other Aβ variants initiate neuronal damage as soluble species. Indeed, soluble oligomeric Aβ species are considered to exert higher neurotoxicity as compared to fibrillar assemblies in extracellular plaques [67][68][69].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models

Kumar

Lemere

Walter

2020

acta neuropathol commun

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The deposition of neurotoxic amyloid-β (Aβ) peptides in extracellular plaques in the brain parenchyma is one of the most prominent neuropathological features of Alzheimer's disease (AD), and considered to be closely related to the pathogenesis of this disease. A number of recent studies demonstrate the heterogeneity in the composition of Aβ deposits in AD brains, due to the occurrence of elongated, truncated and post-translationally modified Aβ peptides that have peculiar characteristics in aggregation behavior and biostability. Importantly, the detection of modified Aβ species has been explored to characterize distinct stages of AD, with phosphorylated Aβ being present in the clinical phase of AD. People with Down syndrome (DS) develop AD pathology by 40 years of age likely due to the overproduction of Aβ caused by the additional copy of the gene encoding the amyloid precursor protein on chromosome 21. In the current study, we analysed the deposition of phosphorylated and non-phosphorylated Aβ species in human DS, AD, and control brains. In addition, deposition of these Aβ species was analysed in brains of a series of established transgenic AD mouse models using phosphorylation-state specific Aβ antibodies. Significant amounts of Aβ phosphorylated at serine residue 8 (pSer8Aβ) and unmodified Aβ were detected in the brains of DS and AD cases. The brains of different transgenic mouse models with either only human mutant amyloid precursor protein (APP), or combinations of human mutant APP, Presenilin (PS), and tau transgenes showed distinct agedependent and spatiotemporal deposition of pSer8Aβ in extracellular plaques and within the vasculature. Together, these results demonstrate the deposition of phosphorylated Aβ species in DS brains, further supporting the similarity of Aβ deposition in AD and DS. Thus, the detection of phosphorylated and other modified Aβ species could contribute to the understanding and dissection of the complexity in the age-related and spatiotemporal deposition of Aβ variants in AD and DS as well as in distinct mouse models.

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“…In contrast, the use of anti-PrPC antibodies did not impair LTP (long-term synaptic enhancement) in the presence of soluble Aβ oligomers. This suggests the involvement of PrPC in synaptotoxicity associated with Aβ oligomers [33]. Sengupta et al in their work emphasize that Aβ oligomers act as seeds for various proteins, including PrPC, leading to the formation of toxic aggregates.…”

Section: Subject Of the Study Dose Effect Referencementioning

confidence: 96%

Neuroprotective Properties of Resveratrol and Its Derivatives—Influence on Potential Mechanisms Leading to the Development of Alzheimer’s Disease

Wiciński

Domanowska

Wódkiewicz

et al. 2020

IJMS

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The lack of effective Alzheimer's disease treatment is becoming a challenge for researchers and prompts numerous attempts to search for and develop better therapeutic solutions. Compounds that affect several routes of the neurodegeneration cascade leading to the development of disease are of particular interest. An example of such substances is resveratrol and its synthetic and natural derivatives, which have gained popularity in recent years and show promise as a possible new therapeutic option in the approach to Alzheimer's disease treatment. In this article, the state of the art evidence on the role of resveratrol (RSV) in neuroprotection is presented; research results are summarized and the importance of resveratrol and its derivatives in the treatment of Alzheimer's disease are underlined. It also focuses on various modifications of the resveratrol molecule that should be taken into account in the design of future research on drugs against Alzheimer's disease.

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A mechanistic hypothesis for the impairment of synaptic plasticity by soluble Aβ oligomers from Alzheimer’s brain

Cited by 191 publications

References 182 publications

Age-Dependent Shift of AMPA Receptors From Synapses to Intracellular Compartments in Alzheimer’s Disease: Immunocytochemical Analysis of the CA1 Hippocampal Region in APP/PS1 Transgenic Mouse Model

Age-Dependent Shift of AMPA Receptors From Synapses to Intracellular Compartments in Alzheimer’s Disease: Immunocytochemical Analysis of the CA1 Hippocampal Region in APP/PS1 Transgenic Mouse Model

Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer’s-like mouse models

Neuroprotective Properties of Resveratrol and Its Derivatives—Influence on Potential Mechanisms Leading to the Development of Alzheimer’s Disease

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