Necroptosis activation in Alzheimer's disease

Caccamo, Antonella; Branca, Caterina; Piras, Ignazio S.; Ferreira, Eric; Huentelman, Matthew J.; Liang, Winnie S.; Readhead, Benjamin; Dudley, Joel T.; Spangenberg, Elizabeth E.; Green, Kim N.; Belfiore, Ramona; Winslow, Wendy; Oddo, Salvatore

doi:10.1038/nn.4608

Cited by 318 publications

(321 citation statements)

References 75 publications

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“…In addition, blocking/reducing necroptosis appears to have an impact on the aging of the male reproductive system (Li et al., 2017) and increases the lifespan of ApoE knockout mice (Meng et al., 2015) and G93A transgenic mouse model of ALS (Ito et al., 2016). Necroptosis also appears to play a role in neuron loss in Alzheimer's disease (Caccamo et al., 2017). …”

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confidence: 99%

“…The transcript levels of RIPK3 were similar in adult, old and old‐DR mice; however, the level of RIPK1 transcript was increased in eWAT of old mice (2.3‐fold) (Figure 1b). A similar increase in the transcript levels of RIPK1 and MLKL was reported in the brain of patients with AD (Caccamo et al., 2017). Under conditions of necroptotic cell death, ESCRT‐III controls the duration of plasma membrane integrity (Gong et al., 2017).…”

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Necroptosis increases with age and is reduced by dietary restriction

et al. 2018

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SummaryNecroptosis is a newly identified programmed cell death pathway that is highly proinflammatory due to the release of cellular components that promote inflammation. To determine whether necroptosis might play a role in inflammaging, we studied the effect of age and dietary restriction (DR) on necroptosis in the epididymal white adipose tissue (eWAT), a major source of proinflammatory cytokines. Phosphorylated MLKL and RIPK3, markers of necroptosis, were increased 2.7‐ and 1.9‐fold, respectively, in eWAT of old mice compared to adult mice, and DR reduced P‐MLKL and P‐RIPK3 to levels similar to adult mice. An increase in the expression of RIPK1 (1.6‐fold) and MLKL (2.7‐fold), not RIPK3, was also observed in eWAT of old mice, which was reduced by DR in old mice. The increase in necroptosis was paralleled by an increase in 14 inflammatory cytokines, including the pro‐inflammatory cytokines IL‐6 (3.9‐fold), TNF‐α (4.7‐fold), and IL‐1β (5.1‐fold)], and 11 chemokines in old mice. DR attenuated the expression of IL‐6, TNF‐α, and IL‐1β as well as 85% of the other cytokines/chemokines induced with age. In contrast, inguinal WAT (iWAT), which is less inflammatory, did not show any significant increase with age in the levels of P‐MLKL and MLKL or inflammatory cytokines/chemokines. Because the changes in biomarkers of necroptosis in eWAT with age and DR paralleled the changes in the expression of pro‐inflammatory cytokines, our data support the possibility that necroptosis might play a role in increased chronic inflammation observed with age.

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confidence: 99%

Necroptosis increases with age and is reduced by dietary restriction

et al. 2018

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“…As a subtype of necrosis, necroptosis was initially observed following cellular inflammatory events. The intracellular machinery that activates necroptosis is composed of three key components, namely RIPK1 (receptor‐interacting serine/threonine kinase 1), RIPK3 (receptor‐interacting serine/threonine kinase 3), and MLKL (mixed lineage kinase domain‐like pseudokinase) (Caccamo, Branca, Piras, Ferreira, & Huentelman, 2017; Chen et al., 2016). RIPK1 and RIPK3 are essential components that form necrosomes ahead of the activation of necroptosis.…”

Section: Necrosis: Autophagy‐related Cell Death That Contributes To Tmentioning

confidence: 99%

“…RIPK1 and RIPK3 are essential components that form necrosomes ahead of the activation of necroptosis. The formation of necrosomes triggers necroptosis by activating and phosphorylating MLKL, which culminates in mitochondrial uncoupling, lipid peroxidation, and cell death (Caccamo et al., 2017). …”

Section: Necrosis: Autophagy‐related Cell Death That Contributes To Tmentioning

confidence: 99%

“…On the other hand, necroptosis likewise contributes to neuronal death of Alzheimer's disease. Enhanced activity of RIPK1 is observed in AD‐affected regions, and lowering the activation of necroptosis has been shown to reduce cell loss in mouse models (Caccamo et al., 2017). However, mechanisms that induce the activation of necroptosis remain unclear.…”

Section: Necrosis: Autophagy‐related Cell Death That Contributes To Tmentioning

confidence: 99%

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The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

et al. 2018

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Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.

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DNL104, a Centrally Penetrant RIPK1 Inhibitor, Inhibits RIP1 Kinase Phosphorylation in a Randomized Phase I Ascending Dose Study in Healthy Volunteers

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et al. 2019

Clin Pharma and Therapeutics

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Receptor‐interacting serine/threonine‐protein kinase 1 (RIPK1) regulates inflammation, cytokine release, and necroptotic cell death and is implicated in pathogenic cellular pathways in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis. Inhibition of RIPK1 activity protects against inflammation and cell death in multiple animal models. DNL104 is a selective, brain‐penetrant inhibitor of RIPK1 phosphorylation in clinical development for AD and ALS. DNL104 was tested in 68 healthy volunteers to investigate safety and tolerability, pharmacokinetic profile in plasma and cerebrospinal fluid, and pharmacodynamic effects of RIPK1 inhibition in peripheral blood mononuclear cells in a first‐in‐human, placebo‐controlled, double‐blind, randomized single‐ascending dose (SAD) and multiple‐ascending dose (MAD) study. DNL104 was well‐tolerated in the SAD group and during the dosing period of the MAD group. However, postdose liver toxicity in 37.5% of subjects was observed in the MAD, and assessed to be drug related. We demonstrate that DNL104 leads to RIP1 kinase inhibition, and this is not associated with central nervous system (CNS) toxicities, supporting future development of CNS penetrant RIPK1 inhibitors.

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Necroptosis activation in Alzheimer's disease

Cited by 318 publications

References 75 publications

Necroptosis increases with age and is reduced by dietary restriction

Necroptosis increases with age and is reduced by dietary restriction

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

DNL104, a Centrally Penetrant RIPK1 Inhibitor, Inhibits RIP1 Kinase Phosphorylation in a Randomized Phase I Ascending Dose Study in Healthy Volunteers

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