Ion channel formation by N-terminally truncated Aβ (4–42): relevance for the pathogenesis of Alzheimer's disease

Karkisaval, Abhijith G; Rostagno, Agueda; Azimov, Rustam; Ban, Deependra Kumar; Ghiso, Jorge; Kagan, Bruce L.; Lal, Ratnesh

doi:10.1016/j.nano.2020.102235

Cited by 11 publications

(17 citation statements)

References 61 publications

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“…These channels are non-selective and can be extremely large [3, 4, 20, 24, 34]. Channel formation is frequently cited as a molecular mechanism underlying AD [2, 6, 14, 15, 18, 19], but it is usually implied that the channels are formed in the plasma membrane, which does not explain many phenomena associated with the disease [45]. Our hypothesis suggests that amyloid membrane channels are formed in lysosomal membranes rather than in plasma membranes.…”

Section: Discussionmentioning

confidence: 99%

“…6). Some beta-amyloid fragments are able to form membrane channels, and some are not [18, 24, 41, 42], so endocytosed beta-amyloid can be degraded by lysosomal proteases into both channel-forming and non-channel-forming fragments (Fig. 6, dichotomy 1).…”

Section: Discussionmentioning

confidence: 99%

“…All subjects were evaluated between June 2010 and February 2019. Amyloid positivity was defined by PET data according to ADNI guidelines as a standard uptake value ratio (SUVR) at or above 1.08 for [18]F-flor-betaben or 1.11 for [18]F-florbetapir, with a higher SUVR indicating a greater amyloid plaque burden. Details regarding PET acquisition are described in previous publications and on the ADNI website (www.adni-info.org).…”

Section: Methodsmentioning

confidence: 99%

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Patients with Alzheimer’s disease have increased cellular amyloid uptake

Zaretsky¹,

Zaretskaia²,

Molkov

2022

Preprint

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Amyloid plaques are the main signature of Alzheimer's disease (AD). Beta-amyloid (Aβ) concentration in cerebrospinal fluid (CSF-Aβ) and the density of amyloid depositions have a strong negative correlation. However, AD patients have lower CSF-Aβ levels compared to cognitively normal people even after accounting for this correlation. The goal of this study was to infer variations of parameters in Aβ metabolism of AD patients that underlie this difference using data from the Alzheimer's Disease Neuroimaging Initiative cohort. We found that AD patients had dramatically increased rates of cellular amyloid uptake compared to individuals with normal cognition (NC). A group with late-onset mild cognitive impairment (LMCI) also exhibited stronger amyloid uptake, however this was less pronounced than in the AD group. Estimated parameters in the early-onset MCI group did not differ significantly from those in the NC group. Aβ cytotoxicity depends on both the amount of peptide internalized by cells and its intracellular degradation into toxic products. Based on our results, we speculate that AD and LMCI are associated with increased cellular amyloid uptake which leads to faster disease progression, whereas the early-onset MCI may be mediated by the increased production of toxic amyloid metabolites.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Patients with Alzheimer’s disease have increased cellular amyloid uptake

Zaretsky¹,

Zaretskaia²,

Molkov

2022

Preprint

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“…Moreover, miR-485-5p overexpression induced the decrease in Aβ42 and Aβ40 concentration and the increase in the number of pericytes. It is known that Aβ deposition is a typical feature of AD pathology [ 37 ]. Thus, we concluded that miR-485-5p alleviates the progression of AD in vivo .…”

Section: Discussionmentioning

confidence: 99%

miR-485-5p alleviates Alzheimer’s disease progression by targeting PACS1

Zhang

et al. 2021

Translational Neuroscience

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Alzheimer’s disease (AD) is a common dementia and a heterogeneous disease. Previous research has validated that microRNAs (miRNAs) are pivotal regulators in the initiation and development of tremendous diseases including AD. MicroRNA-485-5p (miR-485-5p) was reported to be an important participant implicated in several neurological diseases, but its role in AD still needs to be further investigated. In this research, we explored the biological function of miR-485-5p in AD. RT-qPCR revealed that miR-485-5p expression was downregulated in the hippocampus of APP/PS1 mice. Additionally, miR-485-5p overexpression facilitated the learning and memory capabilities of APP/PS1 mice according to Morris water maze test, fear conditioning test, and immunofluorescent staining. Moreover, CCK-8 assay, flow cytometric analysis, and western blot analysis suggested that miR-485-5p overexpression promoted pericyte viability and prohibited pericyte apoptosis in APP/PS1 mice. Mechanistically, miR-485-5p directly targeted PACS1 in pericytes, as shown in a luciferase reporter assay. In rescue assays, PACS1 overexpression countervailed the effect of miR-485-5p overexpression on pericyte viability and apoptosis. In conclusion, miR-485-5p ameliorates AD progression by targeting PACS1.

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“…Peptide oligomerization was also monitored by electron microscopy, as previously described [ 38 , 66 , 71 ]. Five microliters of either monomeric or oligomeric preparations of the different Aβ peptides were placed onto carbon-coated 400 mesh Cu/Rh grids (Ted Pella, Inc., Redding, CA) and stained with 1% uranyl acetate in distilled water (Polysciences, Inc., Warrington, PA).…”

Section: Methodsmentioning

confidence: 99%

N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology

Rostagno

Cabrera

Lashley

et al. 2022

Transl Neurodegener

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Background The molecular heterogeneity of Alzheimer’s amyloid-β (Aβ) deposits extends well beyond the classic Aβ1-40/Aβ1-42 dichotomy, substantially expanded by multiple post-translational modifications that increase the proteome diversity. Numerous truncated fragments consistently populate the brain Aβ peptidome, and their homeostatic regulation and potential contribution to disease pathogenesis are largely unknown. Aβ4-x peptides have been reported as major components of plaque cores and the limited studies available indicate their relative abundance in Alzheimer’s disease (AD). Methods Immunohistochemistry was used to assess the topographic distribution of Aβ4-x species in well-characterized AD cases using custom-generated monoclonal antibody 18H6—specific for Aβ4-x species and blind for full-length Aβ1-40/Aβ1-42—in conjunction with thioflavin-S and antibodies recognizing Aβx-40 and Aβx-42 proteoforms. Circular dichroism, thioflavin-T binding, and electron microscopy evaluated the biophysical and aggregation/oligomerization properties of full-length and truncated synthetic homologues, whereas stereotaxic intracerebral injections of monomeric and oligomeric radiolabeled homologues in wild-type mice were used to evaluate their brain clearance characteristics. Results All types of amyloid deposits contained the probed Aβ epitopes, albeit expressed in different proportions. Aβ4-x species showed preferential localization within thioflavin-S-positive cerebral amyloid angiopathy and cored plaques, strongly suggesting poor clearance characteristics and consistent with the reduced solubility and enhanced oligomerization of their synthetic homologues. In vivo clearance studies demonstrated a fast brain efflux of N-terminally truncated and full-length monomeric forms whereas their oligomeric counterparts—particularly of Aβ4-40 and Aβ4-42—consistently exhibited enhanced brain retention. Conclusions The persistence of aggregation-prone Aβ4-x proteoforms likely contributes to the process of amyloid formation, self-perpetuating the amyloidogenic loop and exacerbating amyloid-mediated pathogenic pathways.

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Ion channel formation by N-terminally truncated Aβ (4–42): relevance for the pathogenesis of Alzheimer's disease

Cited by 11 publications

References 61 publications

Patients with Alzheimer’s disease have increased cellular amyloid uptake

Patients with Alzheimer’s disease have increased cellular amyloid uptake

miR-485-5p alleviates Alzheimer’s disease progression by targeting PACS1

N-terminally truncated Aβ4-x proteoforms and their relevance for Alzheimer’s pathophysiology

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