Amyloid β production along the neuronal secretory pathway: Dangerous liaisons in the Golgi?

Fourrière, Lou; Gleeson, Paul A.

doi:10.1111/tra.12808

Cited by 15 publications

(10 citation statements)

References 109 publications

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“…Although often overlooked, the production of Aβ occurs intracellularly following endosomal APP cleavage via β-secretase [57] and sequential γ-secretase processing within either Golgi [58] or lysosomal [59] compartments. Whilst the majority of Aβ is trafficked to the extracellular space, age-related changes in the relative production of Aβ peptide length [60] and disease alterations to trafficking mechanisms, such as Rab GTPases [61, 62], may act synergically to enhance the retention of intracellularly produced Aβ and or indeed its reuptake, leading to its intracellular accumulation [63].…”

Section: Discussionmentioning

confidence: 99%

Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains

Malik,

Miah,

Galgani

et al. 2023

Preprint

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The amyloid cascade hypothesis states that Aβ and its aggregates induce pathological changes in tau, leading to formation of neurofibrillary tangles (NFTs) and cell death. A caveat with this hypothesis is the temporo-spatial divide between plaques and NFTs. This has been addressed by the inclusion of soluble species of Aβ and tau in the revised amyloid cascade hypothesis, however, the demonstration of a correlative relationship between Aβ and tau burden in post-mortem human tissue has remained elusive. Employing frozen and fixed frontal cortex grey and associated white matter tissue from non-AD controls (Con; n=39) and Alzheimer’s diseases (AD) cases (n=21), biochemical and immunohistochemical measures of Aβ and AT-8 phosphorylated tau were assessed. Native-state dot-blot from crude tissue lysates demonstrated robust correlations between intraregional Aβ and AT-8 tau, such increases in Aβ immunoreactivity conferred increases in AT-8 immunoreactivity, both when considered across the entire cohort as well as separately in Con and AD cases. In contrast, no such association between Aβ plaques and AT-8 were reported when using immunohistochemical measurements. However, when using the non-amyloid precursor protein cross reactive MOAB-2, antibody to measure intracellular Aβ within a subset of cases, a similar correlative relationship with AT-8 tau as that observed in biochemical analysis was observed. Collectively our data suggests that accumulating intracellular Aβ may influence AT-8 pathology. Despite the markedly lower levels of phospho-tau in non-AD controls correlative relationships between AT-8 phospho-tau and Aβ as measured in both biochemical and immunohistochemical assays were more robust in non-AD controls, suggesting a physiological association of Aβ production and tau phosphorylation, at least within the frontal cortex. Such interactions between regional Aβ load and phospho-tau load may become modified with disease potentially, as a consequence of interregional tau seed propagation, and thus may diminish the linear relationship observed between Aβ and phospho-tau in non-AD controls. This study provides evidence supportive of the revised amyloid cascade hypothesis, and demonstrates an associative relationship between AT-8 tau pathology and intracellular Aβ but not extracellular Aβ plaques.

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Section: Discussionmentioning

confidence: 99%

Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains

Malik,

Miah,

Galgani

et al. 2023

Preprint

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“…Excessive production of the neurotoxic Aβ peptide from the amyloid precursor protein (APP) cleavage is done by β-secretase, which is the rate-limiting enzyme in this process [ 60 ]. Therefore, the down-regulation of the β-secretase expression inhibits Aβ generation [ 61 ]. In our study, the Scop up-regulated the hippocampal Aβ and β-secretase expression compared with the control group.…”

Section: Discussionmentioning

confidence: 99%

The Potential Neuroprotective Effect of Cyperus esculentus L. Extract in Scopolamine-Induced Cognitive Impairment in Rats: Extensive Biological and Metabolomics Approaches

et al. 2022

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The aim of the present study is to investigate the phytochemical composition of tiger nut (TN) (Cyperus esculentus L.) and its neuroprotective potential in scopolamine (Scop)-induced cognitive impairment in rats. The UHPLC-ESI-QTOF-MS analysis enabled the putative annotation of 88 metabolites, such as saccharides, amino acids, organic acids, fatty acids, phenolic compounds and flavonoids. Treatment with TN extract restored Scop-induced learning and memory impairments. In parallel, TN extract succeeded in lowering amyloid beta, β-secretase protein expression and acetylcholine esterase (AChE) activity in the hippocampus of rats. TN extract decreased malondialdehyde levels, restored antioxidant levels and reduced proinflammatory cytokines as well as the Bax/Bcl2 ratio. Histopathological analysis demonstrated marked neuroprotection in TN-treated groups. In conclusion, the present study reveals that TN extract attenuates Scop-induced memory impairments by diminishing amyloid beta aggregates, as well as its anti-inflammatory, antioxidant, anti-apoptotic and anti-AChE activities.

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“…We also found Mint1 Y633A expressing neurons showed a greater number of neurons with a condensed Golgi morphology compared to Mint1 WT and Mint1 Y459A/F520A mutant. Since the Golgi has been implicated as a site for amyloidogenic APP processing (Fourriere and Gleeson, 2021), and alterations in Golgi morphology are a preclinical feature that occurs before neurodegeneration associated with AD (Dal Canto, 1996; Stieber et al, 1996), it is possible that Mints could also function in APP processing at the Golgi. Neurons expressing Mint1 Y549A/F610A showed a decrease in APP endocytosis and Aβ release when compared to both Mint1 WT and Mint1 Y633A .…”

Section: Discussionmentioning

confidence: 99%

Tight control of the APP-Mint1 interaction in regulating amyloid production

Henry

Bartling

Strømgaard

et al. 2022

Preprint

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Generation of amyloid-beta (Aβ) peptides through the proteolytic processing of the amyloid precursor protein (APP) is one pathogenic event in Alzheimer's disease (AD). APP is a type I transmembrane protein and endocytosis of APP mediated by the endocytic YENPTY sequence is a key step in Aβ generation. We and others have found that Mints, a family of cytosolic adaptor proteins, directly binds to the YENPTY motif of APP via phosphotyrosine binding (PTB) domain of Mints, facilitates APP trafficking and processing. We also show mutation of Tyr633 of Mint1 (Mint1Y633A) enhances APP binding and processing. Now, we created a low-affinity Mint1 mutant that targets two conserved residues, Tyr549 and Phe610 (Mint1Y549A/F610A), that reduced APP binding. Here, we investigate how perturbing the APP-Mint1 interaction alters APP and Mint1 cellular dynamics as well as Mint1's interaction with its other binding partners. We show that Mint1Y633A increased binding affinity specifically for APP and presenilin1, enhanced APP endocytosis, and Aβ secretion in primary neurons. Conversely, Mint1Y549A/F610A exhibited reduced APP affinity and Aβ secretion. In fact, the effect of Mint1Y549A/F610A on Aβ release was greater compared to knocking down all three Mint proteins, supporting targeting APP-Mint1 interaction as a potential AD therapeutic.

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Amyloid β production along the neuronal secretory pathway: Dangerous liaisons in the Golgi?

Cited by 15 publications

References 109 publications

Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains

Post-mortem AT-8 reactive tau species correlate with non-plaque Aβ levels in the frontal cortex of non-AD and AD brains

The Potential Neuroprotective Effect of Cyperus esculentus L. Extract in Scopolamine-Induced Cognitive Impairment in Rats: Extensive Biological and Metabolomics Approaches

Tight control of the APP-Mint1 interaction in regulating amyloid production

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