In vivo induction of membrane damage by β-amyloid peptide oligomers

Julien, Carl; Tomberlin, Colson; Roberts, Christine M.; Akram, Aumbreen; Stein, Gretchen H.; Silverman, Michael; Link, Christopher D.

doi:10.1186/s40478-018-0634-x

Cited by 36 publications

(34 citation statements)

References 91 publications

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“…Therefore, the overexpression of APP and amyloid deposition might be the result of an acute-phase response to neuronal damage. In recent years, the Aβ oligomer hypothesis, which states that oligomers are the initiating pathologic agents in Alzheimer’s disease, has all but supplanted the amyloid cascade hypothesis, which suggested that fibers were the key etiologic agents in Alzheimer’s disease [29,30,31,32]. There is also a growing body of evidence indicating that vascular dysfunction plays a pivotal role in the development of AD.…”

Section: Discussionmentioning

confidence: 99%

Risk of Dementia in Patients with Leptospirosis: A Nationwide Cohort Analysis

Chiu

Chen

Wang

et al. 2019

IJERPH

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Background: Studies have linked some bacterial infections with an increased likelihood for development of dementia. However, there is a paucity of data on the relationship between dementia and leptospirosis. In view of this, we conducted a retrospective cohort study to determine whether leptospirosis is a risk factor for dementia. Methods: Data were collected from the Taiwan National Health Insurance Research Databases (2000–2010) to investigate the incidence of and risk factors for dementia in patients with leptospirosis. Patients with leptospirosis who did not have a history of dementia were enrolled in the study. For each leptospirosis patient, four controls were randomly selected after frequency matching of age, sex, and index date. Cox proportional hazard regression models were used for the analyses of dementia risk. Results: A greater risk of dementia was observed in the leptospirosis cohort than in the non-leptospirosis cohort both in patients without any comorbidity (adjusted HR (aHR) = 1.23, 95% CI = 1.06–1.43) and with a comorbidity (aHR = 2.06, 95% CI = 1.7–2.5). Compared with the non-leptospirosis cohort without these comorbidities, the leptospirosis cohort with ≥2 comorbidities exhibited a significantly increased risk of dementia (aHR = 6.11, 95% CI = 3.15–11.9), followed by those with any one comorbidity (adjusted HR = 3.62, 95% CI = 1.76–7.46). Conclusions: Patients with leptospirosis were at a 1.89-fold greater risk of subsequent dementia, but potential genetic susceptibility bias in the study group is a major confound.

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Section: Discussionmentioning

confidence: 99%

Risk of Dementia in Patients with Leptospirosis: A Nationwide Cohort Analysis

Chiu

Chen

Wang

et al. 2019

IJERPH

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“…The analysis of Lee et al ( 2017 ) has shown structure and conductance of oligomeric Aβ pores in a natural lipid membrane, which closely mimics the in vivo cellular environment. Recent studies also include interaction of Aβ with cellular membranes (Bode et al, 2017 ) and animal models (Julien et al, 2018 ), both confirming the hypothesis of membrane perforation. For example, in C. elegans the membrane repair response was turned on when Aβ was fed to animals (Julien et al, 2018 ).…”

Section: Introductionmentioning

confidence: 70%

Prediction of Transmembrane Regions, Cholesterol, and Ganglioside Binding Sites in Amyloid-Forming Proteins Indicate Potential for Amyloid Pore Formation

Venko

Novič

Stoka

et al. 2021

Front. Mol. Neurosci.

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Besides amyloid fibrils, amyloid pores (APs) represent another mechanism of amyloid induced toxicity. Since hypothesis put forward by Arispe and collegues in 1993 that amyloid-beta makes ion-conducting channels and that Alzheimer's disease may be due to the toxic effect of these channels, many studies have confirmed that APs are formed by prefibrillar oligomers of amyloidogenic proteins and are a common source of cytotoxicity. The mechanism of pore formation is still not well-understood and the structure and imaging of APs in living cells remains an open issue. To get closer to understand AP formation we used predictive methods to assess the propensity of a set of 30 amyloid-forming proteins (AFPs) to form transmembrane channels. A range of amino-acid sequence tools were applied to predict AP domains of AFPs, and provided context on future experiments that are needed in order to contribute toward a deeper understanding of amyloid toxicity. In a set of 30 AFPs we predicted their amyloidogenic propensity, presence of transmembrane (TM) regions, and cholesterol (CBM) and ganglioside binding motifs (GBM), to which the oligomers likely bind. Noteworthy, all pathological AFPs share the presence of TM, CBM, and GBM regions, whereas the functional amyloids seem to show just one of these regions. For comparative purposes, we also analyzed a few examples of amyloid proteins that behave as biologically non-relevant AFPs. Based on the known experimental data on the β-amyloid and α-synuclein pore formation, we suggest that many AFPs have the potential for pore formation. Oligomerization and α-TM helix to β-TM strands transition on lipid rafts seem to be the common key events.

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“…A robust counter-argument to this is that post-mortem samples from Alzheimer’s patients exhibited an almost indistinguishable LC α3-GABA A Rs expression profile to that observed in APP-PSEN1 samples. Indeed, in both mouse and human samples, a significant component of α3 immunoreactivity was located within cytoplasmic compartments, rather than the conventional enrichment on plasma membranes, suggesting that such altered trafficking of these receptors are a phenomenon of the disease itself, rather than the animal model; Finally, a more straightforward explanation could be AβO-mediated damage to the plasma membrane (Julien et al 2018), which simply imposes space constraints for receptor insertion.…”

Section: Discussionmentioning

confidence: 99%

Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

Kelly

Seifi

et al. 2020

Preprint

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Amyloid β oligomers (AβO) are potent modulators of two key Alzheimer's pathological processes, namely synaptic dysfunction and tau tangle formation in various brain regions. Remarkably, the impact of AβO in one of the earliest brain regions to exhibit Alzheimer's pathology, the locus coeruleus (LC), remains to be determined. Of particular importance is the effect of AβO on the excitability of individual LC neurons. This parameter determines brain-wide noradrenaline (NA) release, and thus NA-mediated brain functions, including cognition, emotion and immune function, which are all severely compromised in Alzheimer's. Using a mouse model of increased Aβ production (APP-PSEN1), together with correlative histopathological analyses in post mortem Alzheimer's patient samples, we determined the impact of Aβ pathology on various correlates of LC neuronal integrity. AβO immunoreactivity in the LC of APP-PSEN1 mice was replicated in patient samples, presenting as individual clusters located both intraneuronally, in mitochondrial compartments, as well as extracellularly in association with inhibitory synapses. No specific signal was detected in either patient control or wild type mouse samples. Accompanying this AβO expression profile was LC neuronal hyperexcitability and indicators of oxidative stress in APP-PSEN1 mice. LC hyperexcitability arose from a diminished inhibitory effect of GABA, due to impaired expression and function of the GABA-A receptor (GABA A R) α 3 subunit. Importantly, this altered LCα 3-GABA A R expression profile overlapped with AβO expression in both APP-PSEN1 mice and Alzheimer's patient samples. Finally, strychninesensitive glycine receptors (GlyRs) remained resilient to AβO-induced changes and their activation reversed LC hyperexcitability. Alongside this first demonstration of 4 AβO expression in the LC of Alzheimer's patients, the study is also first to reveal a direct association between AβO and LC neuronal excitability. GlyR-α3-GABA A R modulation of AβO-dependent LC hyperexcitability could delay the onset of cognitive and psychiatric symptoms arising from LC-NA deficits, thereby significantly diminishing the disease burden for Alzheimer's patients. particular relevance to the LC, and its early presentation of Alzheimer's pathology, is the emerging synergistic role of AβO in tau tangle formation (Pickett et al. 2019; Shin et al. 2019b). Intriguingly, while notable LC neuronal loss, attributed to tauopathy, is a core feature in Alzheimer's (Chan-Palay and Asan 1989), there appears to be discordance between the onset of such pathology, and LC neurodegeneration (Weinshenker 2018). Given such considerable evidence, it is reasonable to speculate that in the LC, initial, pre-symptomatic insults in the form of tau tangle and AβO interactions, cooperate to set in motion a range of pathological changes such as synaptic dysfunction, oxidative stress (De Felice et al. 2007) and altered LC excitability (Sanchez-Padilla et al. 2014). Such changes are likely to prove crucial in terms of the long-term viabili...

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In vivo induction of membrane damage by β-amyloid peptide oligomers

Cited by 36 publications

References 91 publications

Risk of Dementia in Patients with Leptospirosis: A Nationwide Cohort Analysis

Risk of Dementia in Patients with Leptospirosis: A Nationwide Cohort Analysis

Prediction of Transmembrane Regions, Cholesterol, and Ganglioside Binding Sites in Amyloid-Forming Proteins Indicate Potential for Amyloid Pore Formation

Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

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