Neurogranin in Alzheimer's disease and ageing: A human post-mortem study

Saunders, Tyler S.; Gunn, Ciaran; Blennow, Kaj; Kvartsberg, Hlin; Zetterberg, Henrik; Shenkin, Susan D; Cox, Simon R.; Deary, Ian J.; Smith, Colin; King, Declan; Spires‐Jones, Tara L.

doi:10.1016/j.nbd.2023.105991

Cited by 29 publications

(18 citation statements)

References 43 publications

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“…These findings are relevant as they strongly suggest that the increased level of Ng previously observed in the CSF of AD patients might reflect the loss of Ng from the patient's pathological brain. Remarkably, the authors' findings have also revealed that the amount of synapse-associated Ng is associated with cognitive decline [18], validating previous data from other groups [98]. All these works confirm CSF Ng level measurements as an early synaptic default biomarker of AD and a predictor of cognitive decline.…”

Section: Synaptic Dysfunction In Alzheimer's Diseasesupporting

confidence: 86%

“…The amyloid regional distribution detected with PET correlates to the distribution of amyloid deposits observed in autopsies [11][12][13]. ↑ brain tissue postmortem (neuritic plaques) [15] ↑ PET [10] Tau protein ↑ [14] ↑ brain tissue postmortem (neurofibrillary tangles) [15] Neurogranin ↓ * [16] ↑ [17] ↓ brain tissue postmortem [18]…”

mentioning

confidence: 64%

“…Interestingly, CSF Ng level increases are correlated with increases in other synaptic proteins such as PSD-95 and SNAP-25 in AD patients compared with other non-AD neurodegenerative disease patients [91] and have also been significantly correlated with t-tau and p-tau levels as well as with the MMSE state examination in AD patients [97]. A recent paper working with aged postmortem human brain tissues has revealed significantly reduced Ng levels in AD patients with respect to healthy individuals across all brain regions (Table 2) [18]. These findings are relevant as they strongly suggest that the increased level of Ng previously observed in the CSF of AD patients might reflect the loss of Ng from the patient's pathological brain.…”

Section: Synaptic Dysfunction In Alzheimer's Diseasementioning

confidence: 88%

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Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

Santillán-Morales,

Rodriguez-Espinosa,

Muñoz-Estrada

et al. 2024

Brain Sciences

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Alzheimer’s disease (AD), as the main cause of dementia, affects millions of people around the world, whose diagnosis is based mainly on clinical criteria. Unfortunately, the diagnosis is obtained very late, when the neurodegenerative damage is significant for most patients. Therefore, the exhaustive study of biomarkers is indispensable for diagnostic, prognostic, and even follow-up support. AD is a multifactorial disease, and knowing its underlying pathological mechanisms is crucial to propose new and valuable biomarkers. In this review, we summarize some of the main biomarkers described in AD, which have been evaluated mainly by imaging studies in cerebrospinal fluid and blood samples. Furthermore, we describe and propose neuronal precursors derived from the olfactory neuroepithelium as a potential resource to evaluate some of the widely known biomarkers of AD and to gear toward searching for new biomarkers. These neuronal lineage cells, which can be obtained directly from patients through a non-invasive and outpatient procedure, display several characteristics that validate them as a surrogate model to study the central nervous system, allowing the analysis of AD pathophysiological processes. Moreover, the ease of obtaining and harvesting endows them as an accessible and powerful resource to evaluate biomarkers in clinical practice.

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Section: Synaptic Dysfunction In Alzheimer's Diseasesupporting

confidence: 86%

mentioning

confidence: 64%

Section: Synaptic Dysfunction In Alzheimer's Diseasementioning

confidence: 88%

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Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

Santillán-Morales,

Rodriguez-Espinosa,

Muñoz-Estrada

et al. 2024

Brain Sciences

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“…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. 1E) were also found to be significantly downregulated upon NI112 treatment.…”

Section: Resultsmentioning

confidence: 91%

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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“…65 NGN that is a post-synaptic protein has been used as a clinical biomarker and observed to significantly increase with aging-related cognitive decline as well as in AD patients. 66,67 Similarly, NCAM-1 protein which has been associated with synaptic plasticity has now been shown to have a role in neuropathological conditions such as AD, MS, Schizophrenia, and others. 68 Besides cognition, many of these biomarkers have also been implicated and used in the detection of neuromuscular diseases like ALS, MS, and others.…”

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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Neurogranin in Alzheimer's disease and ageing: A human post-mortem study

Cited by 29 publications

References 43 publications

Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

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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