Prion-like seeding and nucleation of intracellular amyloid-β

Olsson, Tomas; Klementieva, Oxana; Gouras, Gunnar K.

doi:10.1016/j.nbd.2018.01.015

Cited by 63 publications

(60 citation statements)

References 45 publications

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“…We speculate that age-related signaling for inhibition of C-terminal trimming by gamma-secretase increases A␤ 45 levels whose hydrophobic properties promote aggregation [Brewer et al, in preparation]. Previous studies have reported that long A␤ peptides A␤ 1-47 and A␤ 1-52 aggregate much faster than even A␤ 42 [74] and that these long A␤s are retained and not secreted from cells [75,76]. Early work proposed dynamic controls of the processing of A␤ to regulate the routing toward intra-versus extracellular accumulation of A␤ [77].…”

Section: Processing and Conclusionmentioning

confidence: 99%

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes

Brewer¹,

Herrera

Philipp

et al. 2020

JAD

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This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iA␤), and the mechanism of an age-related increase in iA␤ in adult AD-model mouse neurons. A new end-specific antibody for A␤ 45 and another for aggregated forms of A␤ provide new insight into the composition of iA␤ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iA␤ levels containing aggregates of A␤ 45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iA␤ was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iA␤ and rapidly increased following a brief metabolic stress with glutamate. A␤PP-CTF, A␤ 45 , and aggregated A␤ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iA␤ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long A␤s by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iA␤ processing may lead to application of countermeasures to prolong dementia-free health span. human clinical trials [4]. Although gamma-secretase inhibitors were screened on the basis of their inhibition of the secretion of A␤, a detailed analysis of the mechanism indicated that Semagacestat slows the tripeptide carboxypeptidase terminal triming of the primary products of gamma-secretase endoproteolysis leading to the accumulation of "long A␤s" ending at residues 45, 46, 48, and 49 of the A␤ sequence (Fig. 1), similar to many of the FAD mutations in presenilin, which interfere with the processivity of the tripeptidase trimming [5][6][7]. These results suggest that the reason that Semagacestat and Avagacestat [8] caused cognitive worsening is the same reason that FAD mutations in presenilins cause early onset

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Section: Processing and Conclusionmentioning

confidence: 99%

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes

Brewer¹,

Herrera

Philipp

et al. 2020

JAD

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“…Overexpression of Aβ and iAβ formation causes different mitochondrial dysfunctions (inner transport, axonal transport of mitochondria, and depletion in the synapses) [133]. iAβs may serve as a template showing intracellularly a prion-like seeding in N2A cell cultures [134].…”

Section: Intracellular Aβ and Extracellular Plaquesmentioning

confidence: 99%

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

2020

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The structural polymorphism and the physiological and pathophysiological roles of two important proteins, β-amyloid (Aβ) and tau, that play a key role in Alzheimer’s disease (AD) are reviewed. Recent results demonstrate that monomeric Aβ has important physiological functions. Toxic oligomeric Aβ assemblies (AβOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aβ (fAβ) form has a very ordered cross-β structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AβOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AβO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AβOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research.

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“…It has been demonstrated in an in vitro cellular model that intracellular oligomers may constitute the seeding unit. Aβ seeding nucleation may be initiated inside the APP-producing cells upon their exposure to FAD brain extract [113]. Furthermore, it has been reported that seeding potency of Aβ is the greatest at the beginning of the Aβ aggregation, as well as concurring with a transient increase of the Aβ 42 /Aβ 40 ratio.…”

Section: Other Neurodegenerative Diseasesmentioning

confidence: 99%

The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases

Rozpędek‐Kamińska

Siwecka

Wawrzynkiewicz

et al. 2020

IJMS

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Higher prevalence of neurodegenerative diseases is strictly connected with progressive aging of the world population. Interestingly, a broad range of age-related, neurodegenerative diseases is characterized by a common pathological mechanism—accumulation of misfolded and unfolded proteins within the cells. Under certain circumstances, such protein aggregates may evoke endoplasmic reticulum (ER) stress conditions and subsequent activation of the unfolded protein response (UPR) signaling pathways via the protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent manner. Under mild to moderate ER stress, UPR has a pro-adaptive role. However, severe or long-termed ER stress conditions directly evoke shift of the UPR toward its pro-apoptotic branch, which is considered to be a possible cause of neurodegeneration. To this day, there is no effective cure for Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), or prion disease. Currently available treatment approaches for these diseases are only symptomatic and cannot affect the disease progression. Treatment strategies, currently under detailed research, include inhibition of the PERK-dependent UPR signaling branches. The newest data have reported that the use of small-molecule inhibitors of the PERK-mediated signaling branches may contribute to the development of a novel, ground-breaking therapeutic approach for neurodegeneration. In this review, we critically describe all the aspects associated with such targeted therapy against neurodegenerative proteopathies.

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Prion-like seeding and nucleation of intracellular amyloid-β

Cited by 63 publications

References 45 publications

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

The PERK-Dependent Molecular Mechanisms as a Novel Therapeutic Target for Neurodegenerative Diseases

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