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- W2074710085 abstract "Nonfibrillar assemblies of amyloid β -protein (A β) are considered to play primary roles in Alzheimer disease (AD). Amylospheroids (ASPDs), AD brain-derived Aβ assemblies, represent a class of highly toxic amyloid assemblies that exhibit spherical morphology with a diameter of ∼10–15 nm in transmission electron microscopy. Our previous studies supported AD-derived ASPD is pathologically relevant to AD because native ASPD isolated from patient brains is indeed toxic to human mature neurons and its level in AD brains correlated well with the pathological severity of AD. These findings suggested ASPD is an effector of amyloid-neurotoxicity in humans. Although we found the ASPD formation occurred in a pathway distinct from the fibril formation, it remained to be elucidated at which place ASPDs are indeed formed. In this work, we examined the location of the ASPD formation to reveal if the formation takes place inside or outside of neurons. To this end, wild type and mutant APP (Swedish and E693 Δ) genes responsible for the familial AD were expressed in rat hippocampal primary neuronal cultures with adeno-associated virus vector. Alien APP was expressed specifically in neurons. It has been reported that abnormal proteins accumulate in the cytoplasm when proteasome activities are compromised with age. We therefore treated the APP-expressing neurons with a proteasome inhibitor, MG132. The immunostaining studies revealed ASPDs were localized in Golgi apparatus, which were inhibited by brefeldin A. This shows ASPD formation takes place specifically in Golgi apparatus. We further found formation of ASPDs in the neurons expressing Swedish APP was faster than wild type APP or E693 Δ. However, interestingly E693 Δ -APP-infected cells have a lower cell viability than wild type APP or Swedish, suggesting a possibility ASPDs formed in the E693 Δ -APP-expressing neurons may have higher toxicity. Surprisingly, ASPD-forming neurons were TUNEL-negative themselves, which were surrounded by TUNEL-positive cells. However these TUNEL-negative ASPD-forming neurons also slowly underwent cell death. We thus succeed to produce toxic ASPDs inside neurons, specifically in Golgi apparatus. Further studies are in progress to elucidate the mechanism of the observed neurotoxicity." @default.
- W2074710085 created "2016-06-24" @default.
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- W2074710085 date "2013-07-01" @default.
- W2074710085 modified "2023-09-27" @default.
- W2074710085 title "P1-076: Formation and neurotoxicity of high-mass beta-amyloid assemblies, amylospheroids, from amyloid precursor proteins in neurons with Alzheimer's mutations" @default.
- W2074710085 doi "https://doi.org/10.1016/j.jalz.2013.05.297" @default.
- W2074710085 hasPublicationYear "2013" @default.
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