The paradigm of amyloid precursor protein in amyotrophic lateral sclerosis: The potential role of the 682YENPTY687 motif

Matrone, Carmela

doi:10.1016/j.csbj.2023.01.008

Cited by 8 publications

(7 citation statements)

References 168 publications

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“…Consistent with previous studies in sporadic ALS [7][8][9][10], the CSF levels of Aβ42 were increased in SOD1-ALS patients and normalised following treatment with tofersen. Since Aβ40 showed a similar trend, our results reinforce the previously reported interplay between SOD1 and Aβ peptides in ALS [11]. In fact, Aβ seems to accumulate in neurons, muscle/neuromuscular junctions and skin of ALS patients, possibly associated with oxidative stress [12][13][14][15].…”

Section: Discussionsupporting

confidence: 90%

Targeted proteomics upon Tofersen identifies candidate response markers for SOD1-linked amyotrophic lateral sclerosis

Steffke,

Baskar,

Wiesenfarth

et al. 2024

Preprint

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Tofersen is the first effective and approved therapy for familial ALS caused by pathogenic variants in the SOD1 gene. Following treatment with tofersen, neurofilaments in patients CSF and serum display a faster response than clinical parameters, underlining their importance as a biomarker for treatment response in clinical trials. This evidence led us to hypothesize that this novel treatment might represent an opportunity to identify additional therapy-responsive biomarkers for ALS. We chose the commercial NUcleic acid Linked Immuno-Sandwich Assay (NULISA), to investigate a predefined panel of 120 neural, glial and inflammatory markers in CSF and serum samples longitudinally collected from SOD1-ALS patients at baseline and three months after tofersen treatment. We identified a set of proteins (beyond pNfH and NfL) whose levels differed between SOD1-ALS and the matched control group and that were responsive to treatment with tofersen, including Amyloid beta 40;42, NPY and UCHL1. Even though our results warrant validation in larger cohorts and longer follow-up time, they may pave the way for a panel of responsive proteins solidifying biomarker endpoints in clinical trials.

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Section: Discussionsupporting

confidence: 90%

Targeted proteomics upon Tofersen identifies candidate response markers for SOD1-linked amyotrophic lateral sclerosis

Steffke,

Baskar,

Wiesenfarth

et al. 2024

Preprint

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“…KLK6 is an important neurodegenerative biomarker shown to be directly linked to axonal and neuronal degeneration and motor function loss, 75 as well as other neuropathologies such as neuroinflammation and Tau phosphorylation leading to identification in other CNS disease biomarkers. 76 Additionally, Aβ42 77 and pTau (pT181), 78 which are associated with AD, were also elevated in ALS 77,78 organoids and reduced to their HMN levels with NI112 treatment. Additional neurodegeneration biomarkers including NCAM-1, 79 Neurogranin (NGN), 80,81 and FGF-21 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Brain-Penetrant NF-κB and NLRP3 Targeting Nanoligomers are Therapeutic in Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s Disease (AD) Human Organoid and Mouse Models

Sharma,

Wahl,

Risen

et al. 2024

Preprint

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Millions of people suffer worldwide from neurodegenerative diseases ranging from rapidly progressing and fatal motor neuron diseases like Amyotrophic Lateral Sclerosis (ALS) to more chronic illnesses such as frontotemporal dementia (FTD) and Alzheimers disease (AD). A growing number of studies have implicated neuroinflammation as a key and causative phenomenon and an important target for novel therapeutics for these diseases. Neuroinflammation is characterized by reactive glial cells that produce pro-inflammatory neurotoxic cytokines. Our previous studies have shown a brain-penetrant Nanoligomer cocktail (NI112) inhibiting the neuroinflammation mediators nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and NOD-like receptor family, pyrin domain containing 3 (NLRP3) is a safe, targeted, and effective neurotherapeutic drug. Here, we show that a four-week NI112 treatment is therapeutic using: 1) an ALS-FTD 3D human motor neuron organoid model of tar DNA binding protein 43 (TDP-43, a key contributor to ALS pathology) overexpression (knock-in); 2) an AD model of APOE4/APOE4 (AD risk allele) double mutation in human neurons comprising a 3D human prefrontal cortex (PFC) organoid; and 3) multiple in vivo (mouse models) of the same/related conditions. In 3D organoids made from healthy motor neurons (HMN negative control) and TDP-43 overexpressing (or ALS organoids), we monitored the mean firing rate using calcium signaling as a functional output, while measuring TDP-43 and other key neurodegeneration biomarkers. After 4 weeks, we observed a massive improvement in the mean firing rate of NI112-treated ALS organoids compared to untreated ALS organoids, which was more comparable to healthy HMN organoids. Similarly, we found a significant decrease in neurodegeneration markers like amyloid beta 42 (Aβ42) in NI112-treated AD organoids compared to untreated AD organoids (Aβ42 comparable to healthy PFC organoids). In the mouse ALS (SOD1-G93A) model, we observed behavioral improvements and restoration of motor function (e.g., grip strength) in NI112-treated mice, and in mouse AD model mice (radiation-induced accelerated neuropathology in APP/PS1, and rTg4510 phospho-tau), we observed improved cognition. In both models, we also found an accompanying reduction in neuroinflammation and reduced neuropathology. These results show the promise for further testing and development of neuroinflammation-targeting Nanoligomers to benefit patients suffering from debilitating neurodegenerative diseases like ALS, FTD, and AD.

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“…68 Besides cognition, many of these biomarkers have also been implicated and used in the detection of neuromuscular diseases like ALS, MS, and others. Typically, while elevated amyloid plaques Aβ42 69 and pTau (pT181) 70 levels are nominally associated with plaques and neurofibrillary tangles as AD pathologies, evidence of increased levels of these proteins have also been documented in neuromuscular diseases like ALS, MS, and others. 69,70 Similarly, pTau and total Tau, 71 TDP-43, 58,72 NCAM-1, 68 and NGN 67 have well-documented roles as broader neurodegeneration biomarkers.…”

Section: Resultsmentioning

confidence: 99%

“…Typically, while elevated amyloid plaques Aβ42 69 and pTau (pT181) 70 levels are nominally associated with plaques and neurofibrillary tangles as AD pathologies, evidence of increased levels of these proteins have also been documented in neuromuscular diseases like ALS, MS, and others. 69,70 Similarly, pTau and total Tau, 71 TDP-43, 58,72 NCAM-1, 68 and NGN 67 have well-documented roles as broader neurodegeneration biomarkers. Therefore, we selected these clinically accepted diagnostic biomarkers to determine if space-induced neuropathology or accelerated neurodegeneration occurred.…”

Section: Resultsmentioning

confidence: 99%

Inflammasome-Inhibiting Nanoligomers are Neuroprotective Against Space-Induced Pathology in Healthy and Diseased 3D Human Motor and Pre-Frontal Cortex Brain Organoids

Sharma,

Gilberto,

Rask

et al. 2024

Preprint

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Microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to space astronauts and tourists, and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here we show, a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station (ISS). First, comparing 3D healthy and diseased pre-frontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimers Disease (AD), Frontotemporal Dementia (FTD), and Amyotrophic Lateral Sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 which targeted NF-κB, and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aβ42), phosphorylated Tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel, and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.

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The paradigm of amyloid precursor protein in amyotrophic lateral sclerosis: The potential role of the 682YENPTY687 motif

Cited by 8 publications

References 168 publications

Targeted proteomics upon Tofersen identifies candidate response markers for SOD1-linked amyotrophic lateral sclerosis

Targeted proteomics upon Tofersen identifies candidate response markers for SOD1-linked amyotrophic lateral sclerosis

Brain-Penetrant NF-κB and NLRP3 Targeting Nanoligomers are Therapeutic in Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s Disease (AD) Human Organoid and Mouse Models

Inflammasome-Inhibiting Nanoligomers are Neuroprotective Against Space-Induced Pathology in Healthy and Diseased 3D Human Motor and Pre-Frontal Cortex Brain Organoids

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