Monoamine alterations in Alzheimer’s disease and their implications in comorbid neuropsychiatric symptoms

GeroScience, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 27, 2024

Language: Английский

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Noradrenaline in Alzheimer’s Disease: A New Potential Therapeutic Target

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 6143 - 6143

Published: May 30, 2022

A growing body of evidence demonstrates the important role noradrenergic system in pathogenesis many neurodegenerative processes, especially Alzheimer’s disease, due to its ability control glial activation and chemokine production resulting anti-inflammatory neuroprotective effects. Noradrenaline involvement this disease was first proposed after finding deficits neurons locus coeruleus from patients. Based on this, it has been hypothesized that early loss projections subsequent reduction noradrenaline brain levels contribute cognitive dysfunctions progression neurodegeneration. Several studies have focused analyzing development disease. In review we summarize some most relevant data describing alterations normally occurring as well experimental which concentration modified order further analyze how these affect behavior viability different nervous cells. The combination here presented suggests maintenance adequate central constitutes a key factor endogenous defense systems help prevent or delay For reason, use modulating drugs is an interesting alternative therapeutic option for

Language: Английский

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Consequences of Hyperphosphorylated Tau in the Locus Coeruleus on Behavior and Cognition in a Rat Model of Alzheimer’s Disease

Journal of Alzheimer s Disease, Journal Year: 2022, Volume and Issue: 86(3), P. 1037 - 1059

Published: Feb. 11, 2022

Background: The locus coeruleus (LC) is one of the earliest brain regions to accumulate hyperphosphorylated tau, but a lack animal models that recapitulate this pathology has hampered our understanding its contributions Alzheimer’s disease (AD) pathophysiology. Objective: We previously reported TgF344-AD rats, which overexpress mutant human amyloid precursor protein and presenilin-1, early endogenous tau in LC. Here, we used rats wild-type (WT) virus interrogate effects rat LC on AD-related neuropathology behavior. Methods: Two-month-old WT received bilateral infusions full-length or mCherry control driven by noradrenergic-specific PRSx8 promoter. Rats were subsequently assessed at 6 12 months for arousal (sleep latency), anxiety-like behavior (open field, elevated plus maze, novelty-suppressed feeding), passive coping (forced swim task), learning memory (Morris water maze fear conditioning). Hippocampal microglia, astrocyte, AD evaluated using immunohistochemistry. Results: In general, age more pronounced than genotype treatment; older displayed greater hippocampal pathology, took longer fall asleep, had reduced locomotor activity, floated more, impaired cognition compared younger animals. showed increased memory. negligible influence most measures. Conclusion: Effects AD-like behavioral symptoms subtle. Further investigation different forms warranted.

Language: Английский

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State-of-the-art imaging of neuromodulatory subcortical systems in aging and Alzheimer’s disease: Challenges and opportunities

Neuroscience & Biobehavioral Reviews, Journal Year: 2022, Volume and Issue: 144, P. 104998 - 104998

Published: Dec. 13, 2022

Language: Английский

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The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease

eNeuro, Journal Year: 2022, Volume and Issue: 10(1), P. ENEURO.0483 - 22.2022

Published: Dec. 9, 2022

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer's disease (AD) Parkinson's (PD), respectively. onset these pathologies coincides with loss fibers LC target regions emergence prodromal symptoms including sleep disturbances anxiety. Paradoxically, are indicative a hyperactivity phenotype, rather than predicted norepinephrine (NE) transmission following damage, suggesting engagement complex compensatory mechanisms. Because current therapeutic efforts targeting early disease, interest has grown, it critical to identify links between dysfunction. We employed LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages axons, model changes LC-NE system pertinent AD PD male female mice. DSP-4 (two doses 50 mg/kg, one week apart) induced axon degeneration, triggered neuroinflammation oxidative stress, reduced tissue NE levels. There was no cell death or firing, but transcriptomics revealed expression genes that define identity other relevant neurodegenerative disease. Despite dramatic fibers, turnover signaling were elevated terminal associated anxiogenic phenotypes multiple behavioral tests. These results represent comprehensive analysis how responds axon/terminal damage reminiscent at molecular, cellular, systems, levels, provides potential mechanisms underlying neuropsychiatric symptoms.

Language: Английский

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Enhancement of neural regeneration as a therapeutic strategy for Alzheimer's disease (Review)

Experimental and Therapeutic Medicine, Journal Year: 2023, Volume and Issue: 26(3)

Published: Aug. 1, 2023

Alzheimer's disease (AD), the most common cause of dementia worldwide, has gradually become a global health concern for society and individuals with process ageing. Although extensive research been carried out on AD, etiology pathological mechanism are still unclear, there is no specific drug to cure or delay AD progression. The exploration enhancing nerve regeneration in attracted increasing attention. In current review, existing therapeutic strategies were summarized induce which can increase number neurons, improve survival plasticity synapses synaptic activity. include neurotrophic expression (such as brain‑derived factor growth factor), inhibiting acetylcholinesterase donepezil, tacrine, rivastigmine galanthamine), elevating histone deacetylase levels RGFP‑966, Tasquinimod, CM‑414 44B), stimulating brain by physiotherapy near‑infrared light, repetitive transcranial magnetic stimulation, direct stimulation) transplanting exogenous neural stem cells. However, further evaluations need be performed determine optimal treatment. present study reviews recent interventions adult neurogenesis attempts elucidate their mechanisms action, may provide theoretical basis inducing fight against AD.

Language: Английский

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An interim exploratory proteomics biomarker analysis of a phase 2 clinical trial to assess the impact of CT1812 in Alzheimer's disease

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 199, P. 106575 - 106575

Published: June 22, 2024

CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that currently in clinical development for treatment Alzheimer's disease (AD). Preclinical and early data show that, through S2R, selectively prevents displaces binding amyloid beta (Aβ) oligomers from neuronal synapses improves cognitive function animal models AD. SHINE an ongoing Phase 2 randomized, double-blind, placebo-controlled trial (COG0201) participants with mild to moderate AD, designed assess safety efficacy 6 months treatment. To elucidate mechanism action AD patients pharmacodynamic biomarkers CT1812, present study reports exploratory cerebrospinal fluid (CSF) biomarker 18 interim analysis first set (part A). Untargeted mass spectrometry-based discovery proteomics detects >2000 proteins patient CSF has documented utility accelerating identification novel reflective diverse pathophysiologies beyond tau, enabling longitudinal interventional trials. We leveraged this technique analyze samples taken at baseline after Proteome-wide protein levels were detected using tandem tag-mass spectrometry (TMT-MS), change was calculated each participant, differential abundance by group performed. This revealed significantly impacted including pathway engagement (i.e., tied S2R biology) modification altered vs. healthy control but normalized correlated favorable trends ADAS-Cog11 scores). Brain network mapping, Gene Ontology, analyses impact on synapses, lipoprotein biology, neuroinflammation. Collectively, findings highlight method providing mechanistic insights which may facilitate enable appropriate pre-specification upcoming trials CT1812.

Language: Английский

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An Expanded Narrative Review of Neurotransmitters on Alzheimer’s Disease: The Role of Therapeutic Interventions on Neurotransmission

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: July 16, 2024

Alzheimer's disease (AD) is a progressive neurodegenerative disease. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles are the key players responsible for pathogenesis Aβ affect balance in chemical neurotransmitters brain. Thus, current review examined role discusses alterations neurochemical activity cross talk with their receptors transporters. In presence tangles, changes may occur expression neuronal which turn triggers excessive release glutamate into synaptic cleft contributing to cell death damage. GABAergic system also be affected by AD pathology similar way. addition, decreased cholinergic dysfunction dopamine neurotransmission contribute damage cognitive function. Moreover, deficiencies noradrenergic neurons within locus coeruleus suggests that stimulation could useful addressing its pathophysiology. regulation melatonin, known effectiveness enhancing function preventing accumulation, along involvement serotonergic histaminergic cognition memory, becomes remarkable promoting AD. Additionally, nitric oxide adenosine-based therapeutic approaches play protective neuroinflammation. Overall, neurotransmitter-based strategies emerge as pivotal neurotransmitter homeostasis context This discussed potential drugs effective slowing correcting processes targeting imbalance Therefore, serve future strategy tackle

Language: Английский

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Ellagic Acid: A Dietary-Derived Phenolic Compound for Drug Discovery in Mild Cognitive Impairment

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: July 4, 2022

Ellagic acid (EA), a naturally occurring polyphenolic compound, is detected in free form or linked to polyols sugars, constituting hydrolyzable tannins ellagitannins distinct fruits, nuts, and herbs. Today, considerable number of botanicals enriched foods containing EA are commercially available as nutraceuticals used prevent mild cognitive impairment (MCI) due the excellent neuroprotective capacity EA. Here, this study aims provide an overview physicochemical properties, source, pharmacokinetics emphasize importance mechanisms prevention management MCI. To date, preclinical studies its derivatives various cell lines animal models have advanced idea dietary feasible agent capable specifically targeting improving The molecular reduce MCI mainly through reducing neuroinflammation, oxidative stress, neuronal apoptosis, synaptic dysfunction loss, defective mitochondrial functions. Nevertheless, well-designed correctly large randomized controlled trials human population need be performed reinforce scientific facticity beneficial effects against Synchronously, mechanism least provided cynosure expects more attention from emerging research community.

Language: Английский

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Noradrenergic neuromodulation in ageing and disease

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 152, P. 105311 - 105311

Published: July 10, 2023

The locus coeruleus (LC) is a small brainstem structure located in the lower pons and main source of noradrenaline (NA) brain. Via its phasic tonic firing, it modulates cognition autonomic functions involved brain's immune response. extent degeneration to LC healthy ageing remains unclear, however, noradrenergic dysfunction may contribute pathogenesis Alzheimer's (AD) Parkinson's disease (PD). Despite their differences progression at later stages, early involvement lead comparable behavioural symptoms such as preclinical sleep problems neuropsychiatric result AD PD pathology. In this review, we draw attention mechanisms that underlie ageing, PD. We aim motivate future research investigate how system play pivotal role which also be relevant other neurodegenerative diseases.

Language: Английский

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