Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis

Roos, Tomas T; Garcia, Megg G; Martinsson, Isak; Mabrouk, Rana; Israelsson, Bodil; Deierborg, Tomas; Kobro‐Flatmoen, Asgeir; Tanila, Heikki; Gouras, Gunnar K.

doi:10.1007/s00401-021-02345-9

Cited by 21 publications

(18 citation statements)

References 47 publications

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“…In a similar prion-like fashion, pathogenic tau harvested from patients can seed endogenous mouse tau and propagate spread (63). A number of studies have demonstrated evidence for both transsynaptic as well as non-synaptic modes of disease progression (63)(64)(65)(66). For example, microglia are capable of releasing extracellular vesicles containing tau aggregates which contribute significantly to non-synaptic spread of pathology (64).…”

Section: Discussionmentioning

confidence: 99%

Role of the caspase-8/RIPK3 axis in Alzheimer’s disease pathogenesis and Aβ-induced NLRP3 inflammasome activation

Kumar¹,

Budhathoki²,

Oliveira³

et al. 2023

JCI Insight

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The molecular mediators of cell death and inflammation in Alzheimer's disease (AD) have yet to be fully elucidated. Caspase-8 is a critical regulator of several cell death and inflammatory pathways; however, its role in AD pathogenesis has not yet been examined in detail. In the absence of Caspase-8, mice are embryonic lethal due to excessive RIPK3-dependent necroptosis. Compound RIPK3 and Caspase-8 mutants rescue embryonic lethality, which we leveraged to examine the roles of these pathways in an amyloid beta (Aβ)-mediated mouse model of AD. We find that combined deletion of Caspase-8 and RIPK3, but not RIPK3 alone, leads to diminished Aβ deposition and microgliosis in the 5xFAD mouse model of AD. Despite its well-known role in cell death, Caspase-8 does not appear to impact cell loss in the 5xFAD model. In contrast, we found that Caspase-8 is a critical regulator of Aβ-driven inflammasome gene expression and IL-1β release. Interestingly, loss of RIPK3 had only a modest effect on disease progression suggesting that inhibition of necroptosis or RIPK3-mediated cytokine pathways are not critical during mid stages of Aβ amyloidosis. These findings suggest that therapeutics targeting Caspase-8 may represent a novel strategy to limit Aꞵ amyloidosis and neuroinflammation in AD.

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Section: Discussionmentioning

confidence: 99%

Role of the caspase-8/RIPK3 axis in Alzheimer’s disease pathogenesis and Aβ-induced NLRP3 inflammasome activation

Kumar¹,

Budhathoki²,

Oliveira³

et al. 2023

JCI Insight

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“…Cellular culture models typically make use of established cell lines of rodent or human origin, or they rely on harvesting primary neurons. The latter are typically obtained from embryonic or early postnatal cortical tissue from rats or mice (Calvo-Rodríguez et al, 2017; Kaech et al, 2006; Konings et al, 2021; Roos et al, 2021; Sahu et al, 2019). However, AD affects subsets of mature neurons, and we may therefore gain insights also by studying cultures of fully developed neurons, for example by harvesting these from adult AD-model animals.…”

Section: Introductionmentioning

confidence: 99%

Microdissection and culturing of adult lateral entorhinal cortex layer II neurons from APP/PS1 Alzheimer model mice

Hanssen

Sandvig

et al. 2022

Preprint

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Background: Primary neuronal cultures enable cell-biological studies of Alzheimer's disease (AD), albeit typically non-neuron-specific. The first cortical neurons affected in AD reside in layer II of the lateralmost part of the entorhinal cortex, and they undergo early accumulation of intracellular amyloid-β, form subsequent tau pathology, and start degenerating pre-symptomatically. These vulnerable entorhinal neurons uniquely express the glycoprotein reelin and provide selective inputs to the hippocampal memory system. Gaining a more direct access to study these neurons is therefore highly relevant. New method: We demonstrate a methodological approach for microdissection and long-term culturing of adult lateral entorhinal layer II-neurons from AD-model mice. Results: We maintain adult microdissected lateralmost entorhinal layer II-neurons beyond two months in culture. We show that they express neuronal markers, and that they are electrophysiologically active by 15 days in vitro and continuing beyond 2 months. Comparison with existing methods: Primary neurons are typically harvested from embryonic or early postnatal brains because such neurons are easier to culture compared to adult neurons. Methods to culture adult primary neurons have been reported, however, to our knowledge, culturing of adult entorhinal subregion-specific primary neurons from AD-model animals has not been reported. Conclusions: Our methodological approach offers a window to study initial pathological changes in the AD disease-cascade. This includes the study of proteinopathy, single-neuron changes, and network-level dysfunction.

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“…A study showed that A β 1–40 induces the release of inflammatory factors and activates oxidative stress in the retina [ 4 , 5 ]. A β 1–40 also has been found to cooperate with neutrophils to trigger cognitive damage in Alzheimer's disease (AD) [ 6 ]. Recently, intravitreal injection of A β 1-40 has replaced subretinal injection and has been used to establish AMD mouse models [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Aβ1–40 Oligomers Trigger Neutrophil Extracellular Trap Formation through TLR4- and NADPH Oxidase-Dependent Pathways in Age-Related Macular Degeneration

Chen

Zhao

Ding

et al. 2022

Oxidative Medicine and Cellular Longevity

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Neutrophils participate in the advancement of the human innate immune system and respond to perceived endogenous and exogenous threats. As a response mechanism, neutrophil extracellular traps (NETs) form near pathogens and surrounding tissues during an immune response. Drusen is an important marker of Age-Related Macular Degeneration (AMD) and plays an important role in the course of AMD. Aβ1-40 is the main component of drusen. However, the relationship between NETs and AMD or Aβ1-40 is unclear. Here, we found elevated levels of NETs in the serum of AMD patients and elevated levels in the serum of mouse models. We also observed the accumulation of neutrophils in the mouse retina. In addition, the production of NETs was inhibited by PAD4 inhibitors, which can alleviate chronic inflammation. Moreover, we confirmed that Aβ1-40 can induce NETs formation via the Toll-like receptor 4 (TLR4) and neutrophil NADPH oxidase (NOX) pathways. Our study confirmed that the formation of NETs is induced by Aβ1–40, and the results suggest that NETs may play a vital role in AMD pathogenesis.

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Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis

Cited by 21 publications

References 47 publications

Role of the caspase-8/RIPK3 axis in Alzheimer’s disease pathogenesis and Aβ-induced NLRP3 inflammasome activation

Role of the caspase-8/RIPK3 axis in Alzheimer’s disease pathogenesis and Aβ-induced NLRP3 inflammasome activation

Microdissection and culturing of adult lateral entorhinal cortex layer II neurons from APP/PS1 Alzheimer model mice

Aβ1–40 Oligomers Trigger Neutrophil Extracellular Trap Formation through TLR4- and NADPH Oxidase-Dependent Pathways in Age-Related Macular Degeneration

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