Aβ dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer's disease

Abdel-Hafiz, Laila; Müller‐Schiffmann, Andreas; Korth, Carsten; Fazari, Benedetta; Chao, Owen Y.; Nikolaus, Susanne; Schäble, Sandra; Herring, Arne; Keyvani, Kathy; Lamounier-Zepter, Valéria; Huston, Joseph P.; Silva, Maria A. de Souza

doi:10.1016/j.neurobiolaging.2018.04.005

Cited by 13 publications

(9 citation statements)

References 56 publications

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“…Aβ dimers are the smallest Aβ aggregates, and they have three characteristics: high levels in the brains of AD patients and transgenic mice [ 121 , 122 , 123 , 124 ], stable in SDS and strong denaturants [ 101 , 104 , 122 , 125 , 126 ], and significant neurotoxicity [ 101 , 102 , 103 , 104 ]. When treated with 6.8M guanidine thiocyanate, the soluble Aβ aggregates and insoluble Aβ plaques in AD brains are dispersed into two bands in SDS gel electrophoresis (SDS-PAGE), such as Aβ monomers and dimers [ 104 , 124 , 125 ].…”

Section: The Polymorphism Of Aβosmentioning

confidence: 99%

“…Adding brain-derived Aβ dimers to primary neurons can reduce the length of neurons [ 101 ], trigger synaptic damage and neuron death, inhibit LTP response and induce tau hyperphosphorylation [ 102 ]. In tgDimer mouse, Aβ dimers contribute to the reduction of hippocampal acetylcholine and serotonin turnover rates, resulting in neurotransmitter dysfunction and behavioral impairments [ 103 ]. The latest study identified that brain-derived Aβ dimers caused neuronal overactivation by inhibiting the glutamate reuptake process.…”

Section: The Polymorphism Of Aβosmentioning

confidence: 99%

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The Toxicity and Polymorphism of β-Amyloid Oligomers

Huang

Liu

2020

IJMS

101

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It is widely accepted that β-amyloid oligomers (Aβos) play a key role in the progression of Alzheimer’s disease (AD) by inducing neuron damage and cognitive impairment, but Aβos are highly heterogeneous in their size, structure and cytotoxicity, making the corresponding studies tough to carry out. Nevertheless, a number of studies have recently made remarkable progress in the describing the characteristics and pathogenicity of Aβos. We here review the mechanisms by which Aβos exert their neuropathogenesis for AD progression, including receptor binding, cell membrane destruction, mitochondrial damage, Ca2+ homeostasis dysregulation and tau pathological induction. We also summarize the characteristics and pathogenicity such as the size, morphology and cytotoxicity of dimers, trimers, Aβ*56 and spherical oligomers, and suggest that Aβos may play a different role at different phases of AD pathogenesis, resulting in differential consequences on neuronal synaptotoxicity and survival. It is warranted to investigate the temporal sequence of Aβos in AD human brain and examine the relationship between different Aβos and cognitive impairment.

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Section: The Polymorphism Of Aβosmentioning

confidence: 99%

Section: The Polymorphism Of Aβosmentioning

confidence: 99%

The Toxicity and Polymorphism of β-Amyloid Oligomers

Huang

Liu

2020

IJMS

101

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“…TgDimer mice are remarkable since they express no insoluble Aβ, hence, do not develop Aβ plaques, astrogliosis or neuroinflammation during their lifetime. Yet they show learning and memory deficits as well as anxiety and despair‐related behaviours with aberrant serotonin and acetylcholine levels and thus reflect features of early AD (14,15).…”

Section: Introductionmentioning

confidence: 99%

The interaction of insoluble Amyloid‐β with soluble Amyloid‐β dimers decreases Amyloid‐β plaque numbers

Gerresheim

Herring

Gremer

et al. 2021

Neuropathology Appl Neurobio

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“…However, recent studies have shown that Aβ dimers, abundantly detected in brains of AD patients, are sufficient to account for neurotoxicity and initiating the amyloid cascade [ 51 , 52 , 53 , 54 ]. Here, we aimed at investigating the effects of the TREM2 R47H mutation in Aβ production as well as the response of CON and AD iPSC-derived neuronal cultures to stimulations with the well described Aβ-S8C dimer [ 55 , 56 , 57 ]. After 4 months of differentiation, neurospheres were dissociated into single cells and differentiated for a further 6 weeks.…”

Section: Resultsmentioning

confidence: 99%

IPSC-Derived Neuronal Cultures Carrying the Alzheimer’s Disease Associated TREM2 R47H Variant Enables the Construction of an Aβ-Induced Gene Regulatory Network

Martins

Müller‐Schiffmann

Erichsen

et al. 2020

IJMS

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Genes associated with immune response and inflammation have been identified as genetic risk factors for late-onset Alzheimer´s disease (LOAD). The rare R47H variant within triggering receptor expressed on myeloid cells 2 (TREM2) has been shown to increase the risk for developing Alzheimer’s disease (AD) 2–3-fold. Here, we report the generation and characterization of a model of late-onset Alzheimer’s disease (LOAD) using lymphoblast-derived induced pluripotent stem cells (iPSCs) from patients carrying the TREM2 R47H mutation, as well as from control individuals without dementia. All iPSCs efficiently differentiated into mature neuronal cultures, however AD neuronal cultures showed a distinct gene expression profile. Furthermore, manipulation of the iPSC-derived neuronal cultures with an Aβ-S8C dimer highlighted metabolic pathways, phagosome and immune response as the most perturbed pathways in AD neuronal cultures. Through the construction of an Aβ-induced gene regulatory network, we were able to identify an Aβ signature linked to protein processing in the endoplasmic reticulum (ER), which emphasized ER-stress, as a potential causal role in LOAD. Overall, this study has shown that our AD-iPSC based model can be used for in-depth studies to better understand the molecular mechanisms underlying the etiology of LOAD and provides new opportunities for screening of potential therapeutic targets.

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Aβ dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer's disease

Cited by 13 publications

References 56 publications

The Toxicity and Polymorphism of β-Amyloid Oligomers

The Toxicity and Polymorphism of β-Amyloid Oligomers

The interaction of insoluble Amyloid‐β with soluble Amyloid‐β dimers decreases Amyloid‐β plaque numbers

IPSC-Derived Neuronal Cultures Carrying the Alzheimer’s Disease Associated TREM2 R47H Variant Enables the Construction of an Aβ-Induced Gene Regulatory Network

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