Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

Kelly, Louise; Seifi, Mohsen; Ma, Ruolin; Mitchell, Stephen J.; Rudolph, Uwe; Viola, Kirsten L.; Klein, William L.; Lambert, Jeremy J.; Swinny, Jerome D.

doi:10.1101/2020.05.14.096396

Cited by 3 publications

(1 citation statement)

References 109 publications

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“…There is evidence for LC hyperactivity in surviving neurons during the degenerative process, resulting in a complex dysregulation of NE transmission. 7,104,105 Importantly, atomoxetine does not just indiscriminately increase synaptic NE levels; it also improves the phasic-to-tonic ratio of LC firing, 52 which is associated with focused attention important for some aspects of learning and memory. Thus, atomoxetine may ameliorate neuroinflammation by increasing NE, while simultaneously improving cognition and behavior by "normalizing" LC activity in the face of pathology and degeneration.…”

Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

Levey

Qiu

Zhao

et al. 2022

Brain

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The locus coeruleus (LC) is the initial site of Alzheimer’s disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. LC dysfunction contributes to Alzheimer’s pathobiology in experimental models, which can be rescued by increasing norepinephrine (NE) transmission. To test NE augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved NE transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer’s disease. The design was a single-center, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment (MCI) and biomarker evidence of Alzheimer’s disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of NE and metabolites. Prespecified primary outcomes were CSF levels of IL1α and Thymus-Expressed Chemokine. Secondary/exploratory outcomes included clinical measures, CSF analyses of Aβ42, Tau, and pTau181, mass spectrometry proteomics, and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and FDG-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF NE levels. IL-1α and Thymus-Expressed Chemokine were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in Aβ42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism, and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK, and OPG proteins. Treatment was also associated with significantly increased BDNF and reduced triglycerides in plasma. Resting state fMRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. FDG-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus, and fusiform gyrus, with carry-over effects six months after treatment. In summary, atomoxetine treatment was safe, well tolerated, and achieved target engagement in prodromal Alzheimer’s disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism, and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer’s disease progression.

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Section: (Which Was Not Certified By Peer Review)mentioning

confidence: 99%

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

Levey

Qiu

Zhao

et al. 2022

Brain

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A Phase II Study Repurposing Atomoxetine for Neuroprotection in Mild Cognitive Impairment

Levey

Qiu

Zhao

et al. 2021

Preprint

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The locus coeruleus (LC) is the initial site of Alzheimer’s disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. LC dysfunction contributes to Alzheimer’s pathobiology in experimental models, which can be rescued by increasing norepinephrine (NE) transmission. To test NE augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved NE transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer’s disease.The design was a single-center, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment (MCI) and biomarker evidence of Alzheimer’s disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of NE and metabolites. Prespecified primary outcomes were CSF levels of IL1α and Thymus-Expressed Chemokine. Secondary/exploratory outcomes included clinical measures, CSF analyses of Aβ42, Tau, and pTau181, mass spectrometry proteomics, and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and FDG-PET.Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF NE levels. IL-1α and Thymus-Expressed Chemokine were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in Aβ42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism, and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK, and OPG proteins. Treatment was also associated with significantly increased BDNF and reduced triglycerides in plasma. Resting state fMRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. FDG-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus, and fusiform gyrus, with carry-over effects six months after treatment.In summary, atomoxetine treatment was safe, well tolerated, and achieved target engagement in prodromal Alzheimer’s disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism, and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer’s disease progression.

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Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease

Patthy

Murai

Hanics

et al. 2021

JCM

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, receives massive afferents from caudal brain structures, which do not only convey specific information but powerfully tune ensemble activity. Moreover, there is evidence that the start of AD is subcortical. The brainstem harbors monoamine systems, which establish a dense innervation in both allo- and neocortex. Monoaminergic synapses can co-release neuropeptides either by precisely terminating on cortical neurons or, when being “en passant”, can instigate local volume transmission. Especially due to its early damage, malfunction of the ascending monoaminergic system emerges as an early sign and possible trigger of AD. This review summarizes the involvement and cascaded impairment of brainstem monoaminergic neurons in AD and discusses cellular mechanisms that lead to their dysfunction. We highlight the significance and therapeutic challenges of transmitter co-release in ascending activating system, describe the role and changes of local connections and distant afferents of brainstem nuclei in AD, and summon the rapidly increasing diagnostic window during the last few years.

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Identification of amyloid beta oligomers in locus coeruleus (LC) neurons of Alzheimer’s patients and their impact on LC oxidative stress, inhibitory neurotransmitter receptors and neuronal excitability

Cited by 3 publications

References 109 publications

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment

A Phase II Study Repurposing Atomoxetine for Neuroprotection in Mild Cognitive Impairment

Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease

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