Dopamine neuron degeneration in the Ventral Tegmental Area causes hippocampal hyperexcitability in experimental Alzheimer’s Disease

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(5), P. 1265 - 1280

Published: Jan. 16, 2024

Abstract Early and progressive dysfunctions of the dopaminergic system from Ventral Tegmental Area (VTA) have been described in Alzheimer’s Disease (AD). During long pre-symptomatic phase, alterations function Parvalbumin interneurons (PV-INs) are also observed, resulting cortical hyperexcitability represented by subclinical epilepsy aberrant gamma-oscillations. However, it is unknown whether deficits contribute to brain AD. Here, using Tg2576 mouse model AD, we prove that reduced hippocampal innervation, due VTA dopamine neuron degeneration, impairs PV-IN firing gamma-waves, weakens inhibition pyramidal neurons induces via lower D2-receptor-mediated activation CREB-pathway. These coincide with numbers Perineuronal Net density. Importantly, L-DOPA selective D2-receptor agonist quinpirole rescue p -CREB levels improve PV-IN-mediated inhibition, thus reducing hyperexcitability. Moreover, similarly quinpirole, sumanirole – another a known anticonvulsant not only increases PV-INs but restores gamma-oscillations mice. Conversely, blocking transmission sulpiride (a D2-like receptor antagonist) WT mice reduces PV-INs, mimicking what occurs Tg2576. Overall, these findings support hypothesis integrity plays key role survival, disclosing relevant contribution tone epileptiform activity early

Language: Английский

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The role of dopamine in NLRP3 inflammasome inhibition: Implications for neurodegenerative diseases

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 87, P. 101907 - 101907

Published: March 8, 2023

Language: Английский

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Digging into the intrinsic capacity concept: Can it be applied to Alzheimer’s disease?

Progress in Neurobiology, Journal Year: 2024, Volume and Issue: 234, P. 102574 - 102574

Published: Jan. 22, 2024

Language: Английский

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Neuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 3, 2024

Abstract The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are earliest sites of tauopathy in Alzheimer’s disease (AD). They project broadly throughout brain’s white matter. We investigated relationship between IdC microstructure and whole-brain matter to better understand early neuropathological changes AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for integrity related 1) neurite density, 2) orientation dispersion tracts known be affected Pattern 2 was associated CSF concentration phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both more strongly than non-carriers. variation is reflected matter, particularly AD-affected tracts, highlighting an mechanism pathological development.

Language: Английский

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Transcranial alternating current stimulation (tACS) at gamma frequency: an up-and-coming tool to modify the progression of Alzheimer’s Disease

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: June 27, 2024

Abstract The last decades have witnessed huge efforts devoted to deciphering the pathological mechanisms underlying Alzheimer’s Disease (AD) and testing new drugs, with recent FDA approval of two anti-amyloid monoclonal antibodies for AD treatment. Beyond these drug-based experimentations, a number pre-clinical clinical trials are exploring benefits alternative treatments, such as non-invasive stimulation techniques on neuropathology symptoms. Among different brain approaches, transcranial alternating current (tACS) is gaining particular attention due its ability externally control gamma oscillations. Here, we outline knowledge concerning efficacy, safety, ease-of-use cost-effectiveness tACS early advanced AD, applied specifically at 40 Hz frequency, also summarise results validated models ongoing patient-centred trials.

Language: Английский

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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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Upregulation of Ca2+-binding proteins contributes to VTA dopamine neuron survival in the early phases of Alzheimer’s disease in Tg2576 mice

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Nov. 25, 2022

Recent clinical and experimental studies have highlighted the involvement of Ventral Tegmental Area (VTA) dopamine (DA) neurons for early pathogenesis Alzheimer's Disease (AD). We previously described a progressive selective degeneration these in Tg2576 mouse model AD, long before amyloid-beta plaque formation. The degenerative process DA is associated with an autophagy flux impairment, whose rescue can prevent neuronal loss. Impairments be basis accumulation damaged mitochondria, leading to disturbance calcium (Ca2+) homeostasis, functional structural deterioration neurons.In mice, we performed amperometric recordings levels analysis dopaminergic fibers Nucleus Accumbens - major component ventral striatum precociously affected AD patients together retrograde tracing, identify most vulnerable neuron subpopulations VTA. Then, focused on analyze mitochondrial integrity Apoptosis-inducing factor (AIF) localization by electron confocal microscopy, respectively. Stereological cell count was also used evaluate containing Ca2+-binding proteins Calbindin-D28K Calretinin. expression were analyzed western blot microscopy. Lastly, using electrophysiology microfluorometry VTA intrinsic properties cytosolic free Ca2+ levels.We found mesolimbic projecting striatum, located paranigral nucleus parabrachial pigmented subnucleus At onset (3 months age), accumulate while AIF translocates from mitochondria nucleus. Although describe age-dependent loss expressing or Calretinin, observed that remaining cells upregulate proteins, are significantly decreased. Coherently, TUNEL-stained express lower when compared non-apoptotic cells.Overall, our results suggest overexpression might attempt survive increasing their ability buffer Ca2+. Exploring strategies overexpress could fundamental reduce suffering improve cognitive non-cognitive functions AD.

Language: Английский

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Meso-cortical pathway damage in cognition, apathy and gait in cerebral small vessel disease

Brain, Journal Year: 2024, Volume and Issue: 147(11), P. 3804 - 3816

Published: May 6, 2024

Abstract Cerebral small vessel disease (SVD) is known to contribute cognitive impairment, apathy and gait dysfunction. Although associations between impairment either or dysfunction have been shown in SVD, the inter-relations among these three clinical features their potential common neural basis remain unexplored. The dopaminergic meso-cortical meso-limbic pathways as important brain circuits for both control, emotion regulation motor function. Here, we investigated dysfunction, with a specific focus on determining whether are associated damage SVD. In this cross-sectional study, included 213 participants SVD whom MRI comprehensive neurobehavioural assessments were performed. These comprised six measures: processing speed, executive function, memory, (based Apathy Evaluation Scale) function time steps Timed Up Go Test). We reconstructed five tracts connecting ventral tegmental area (VTA) dorsolateral prefrontal cortex (PFC), lateral PFC, medial orbitofrontal cortex, anterior cingulate (ACC) nucleus accumbens within using diffusion weighted imaging. along was quantified free water (FW) FW-corrected mean diffusivity indices. Furthermore, explored inter-correlations measures identified components principal component analysis (PCA). Linear regression analyses showed that higher FW values of related cognition, apathy, (all P-corrected < 0.05). PCA strong inter-associations wherein all loaded on. Higher PCA-derived Moreover, VTA-ACC tract strongest contribution over other neuroimaging features. conclusion, our study (cognitive dysfunction) strongly inter-related pathway could be underlying findings advance understanding mechanisms behind inform novel management intervention strategies

Language: Английский

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Malnutrition exacerbating neuropsychiatric symptoms on the Alzheimer's continuum is relevant to the cAMP signaling pathway: Human and mouse studies

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 27, 2025

Abstract INTRODUCTION Malnutrition correlates with neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD); however, the potential mechanism underlying this association remains unclear. METHODS Baseline and longitudinal associations of nutritional status NPSs were analyzed 374 patients on AD continuum 61 healthy controls. Serum biomarkers, behavioral tests, cerebral neurotransmitters, differentially gene expression evaluated standard malnourished diet–fed transgenic APPswe/PSEN1dE9 (APP/PS1) mice. RESULTS Poor increased blood flow midbrain striatum associated severe general subtypes, especially depression, anxiety, apathy. APP/PS1 mice fed a diet showed poor status, depression‐ anxiety‐like behaviors, altered neurotransmitter levels, downregulated c‐Fos striatum; these suppressed cyclic adenosine monophosphate (cAMP) signaling pathway. DISCUSSION exacerbating is relevant to cAMP pathway striatum, suggesting for targeted interventions mitigate continuum. Highlights linked specific symptom (NPS) deterioration. affects NPSs, usually involving striatum. Malnourished induces behaviors exacerbates

Language: Английский

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Dopaminergic deficits along the spectrum of Alzheimer’s disease

Molecular Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Language: Английский

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