Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

Frontiers in Synaptic Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: March 9, 2023

The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, loss is, to date, one of the main biological correlates cognitive decline disease. This occurs prior neuronal with ample evidence that synaptic dysfunction precedes this, in support idea failure is crucial stage disease pathogenesis. two pathological hallmarks abnormal aggregates amyloid or tau proteins, have had demonstrable effects on physiology animal cellular models There also growing these proteins may synergistic effect neurophysiological dysfunction. Here, we review some findings alterations what know from models. First, briefly summarize human suggest synapses are altered, including how this relates network activity. Subsequently, considered, highlighting mouse pathology role play dysfunction, either isolation examining pathologies interact specifically focuses function observed models, typically measured using electrophysiology calcium imaging. Following loss, it would be impossible imagine not alter oscillatory activity brain. Therefore, discusses underpin aberrant patterns seen patients. Finally, an overview key directions considerations field covered. includes current therapeutics targeted at but methods modulate rescue patterns. Other important future avenues note include non-neuronal cell types such as astrocytes microglia, mechanisms independent will certainly continue for foreseeable future.

Language: Английский

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Axonal energy metabolism, and the effects in aging and neurodegenerative diseases

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: July 20, 2023

Abstract Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of (NDAs), such as Alzheimer’s disease, Parkinson’s Huntington’s Amyotrophic lateral sclerosis. Glucose is the major brain fuel glucose hypometabolism has been observed regions vulnerable to NDAs. Many susceptible are topological central hub connectome, linked by densely interconnected long-range axons. Axons, key components have high metabolic needs support neurotransmission other essential activities. Long-range axons particularly injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy often an early sign neurodegeneration. Recent ascribe axonal maintenance failures local dysregulation. With this review, we aim stimulate research exploring metabolically oriented neuroprotection strategies enhance or normalize bioenergetics NDA models. Here start summarizing evidence from human patients animal models reveal correlation between connectomic disintegration aging/NDAs. To encourage mechanistic investigations on how dysregulation occurs during aging/NDAs, first review current literature distinct subdomains: axon initial segments, myelinated arbors harboring pre-synaptic boutons. In each subdomain, focus organization, activity-dependent regulation system, external glial support. Second, mechanisms regulating nicotinamide adenine dinucleotide (NAD + ) homeostasis, molecule for energy metabolism processes, including NAD biosynthetic, recycling, consuming pathways. Third, highlight innate vulnerability connectome discuss its perturbation As deficits developing into NDAs, especially asymptomatic phase, they likely exaggerated further impaired energetic cost neural network hyperactivity, pathology. Future interrogating causal relationship vulnerability, axonopathy, amyloid/tau pathology, cognitive decline will provide fundamental knowledge therapeutic interventions.

Language: Английский

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Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration

Brain, Journal Year: 2024, Volume and Issue: 147(5), P. 1726 - 1739

Published: March 11, 2024

Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis potential mediator of injury as elevations increase excitatory activity. The dysregulation extracellular and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured cortical concentration ([K+]e) in awake wild-type mice well murine models using K+-sensitive microelectrodes. Unexpectedly, aged exhibited significantly lower [K+]e than young mice. In contrast, was consistently elevated Alzheimer's disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) Huntington's (R6/2) models. Cortical resting correlated inversely with density buffering rate but positively predicted firing rate. Screening astrocyte-selective genomic datasets revealed number genes that were downregulated these not particular, inwardly rectifying Kcnj10 ALS ageing, while Fxyd1 Slc1a3, each which acts negative regulator uptake, upregulated by astrocytes both Chronic elevation response changes gene expression attendant hyperexcitability may drive characteristic diseases. These observations suggest be due aberrant astrocytic such, highlight fundamental role for glial dysfunction neurodegeneration.

Language: Английский

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Proteomic changes in Alzheimer disease associated with progressive Aβ plaque and tau tangle pathologies

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(10), P. 1880 - 1891

Published: Aug. 26, 2024

Abstract Proteomics can shed light on the dynamic and multifaceted alterations in neurodegenerative disorders like Alzheimer’s disease (AD). Combining radioligands measuring β-amyloid (Aβ) plaques tau tangles with cerebrospinal fluid proteomics, we uncover molecular events mirroring different stages of AD pathology living humans. We found 127 differentially abundant proteins (DAPs) across spectrum. The strongest Aβ-related were mainly expressed glial cells included SMOC1 ITGAM. A dozen linked to ATP metabolism preferentially neurons independently associated tangle load accumulation. Only 20% DAPs also altered other diseases, underscoring AD’s distinct proteome. Two co-expression modules related, respectively, protein microglial immune response encompassed most DAPs, opposing, staggered trajectories along continuum. unveil signatures Aβ proteinopathy vivo, offering insights into complex neural responses potential biomarkers therapeutics targeting stages.

Language: Английский

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Cortical excitability and the aging brain: toward a biomarker of cognitive resilience

Frontiers in Psychology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 18, 2025

This perspective article addresses the potential use of cortical excitability (CE) as an indicator cognitive health in aging people. Changes CE may be considered a sign resilience to decline old age. The authors describe research on and its link function older adults emphasize that it is promising, non-invasive measure healthy aging. They also address current challenges implementation, need for standardized measurement protocols possible future avenues research. If properly considered, could pave way early detection facilitate targeted interventions promote resilience.

Language: Английский

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Suppression of epileptic seizures by transcranial activation of K+-selective channelrhodopsin

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 10, 2025

Optogenetics is a valuable tool for studying the mechanisms of neurological diseases and now being developed therapeutic applications. In rodents macaques, improved channelrhodopsins have been applied to achieve transcranial optogenetic stimulation. While photoexcitation neurons has achieved, noninvasive inhibition treating hyperexcitability-induced disorders remained elusive. There critical need effective inhibitory tools that are highly light-sensitive capable suppressing neuronal activity in deep brain tissue. this study, we sensitive moderately K+-selective channelrhodopsin (HcKCR1-hs) by molecular engineering recently discovered Hyphochytrium catenoides kalium (potassium) 1. Transcranial activation HcKCR1-hs significantly prolongs time first seizure, increases survival, decreases seizure several status epilepticus mouse models. Our approach neural hyperactivity may be adapted cell type-specific neuromodulation both basic preclinical settings. Optogenetic allowing seizures limited. This study demonstrates K + -conductive silences suppresses brain, alleviating epilepsy symptoms models, without intracranial surgery.

Language: Английский

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Subclinical Epileptiform Discharge in Patients With Alzheimer Dementia: A Systematic Review and Meta-Analysis

Journal of Clinical Neurophysiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 18, 2025

Purpose: Patients with Alzheimer's dementia (AD) who do not have a history of epilepsy higher frequency subclinical epileptiform discharge (SED) than healthy individuals. This meta-analysis aims to investigate the SED in patients AD using different EEG protocols and compare rates between early- late-onset AD. Methods: study adhered Preferred Reporting Items for Systematic Reviews Meta-analysis guidelines. We searched various databases until January 2024 studies reporting did epilepsy. A was conducted random-effects model. Results: Thirteen involving 1,373 were analyzed. The had mean age 71.2 years, 59.3% women. pooled rate found be 18.3%. extended (26.7%) routine (12.1%). It also observed that early-onset (14.4%) (43.9%) those (10.5 21.3%, respectively). Furthermore, 3.55 relative risk ( P < 0.001) compared controls. Specifically, showed significantly developing (relative risk, 4.48; 0.001). Conclusions: Subclinical high AD, particularly early onset

Language: Английский

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Lipid metabolism, remodelling and intercellular transfer in the CNS

Nature reviews. Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Language: Английский

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Detecting Early Cognitive Decline in Alzheimer’s Disease with Brain Synaptic Structural and Functional Evaluation

Biomedicines, Journal Year: 2023, Volume and Issue: 11(2), P. 355 - 355

Published: Jan. 26, 2023

Early cognitive decline in patients with Alzheimer's (AD) is associated quantifiable structural and functional connectivity changes the brain. AD dysregulation of Aβ tau metabolism progressively disrupt normal synaptic function, leading to loss synapses, decreased hippocampal density early atrophy. Advances brain imaging techniques living have enabled transition from clinical signs symptoms-based diagnosis biomarkers-based diagnosis, techniques, quantitative EEG, body fluids sampling. The hippocampus has a central role semantic episodic memory processing. This function critically dependent on intrahippocampal connections many cortical regions, including perirhinal entorhinal cortex, parahippocampal association regions temporal parietal lobes, prefrontal cortex. Therefore, reflected altered intrinsic networks (aka large-scale networks), memory, default mode, salience networks. narrative review discusses recent critical issues related detecting AD-associated markers high-risk or neuropsychologically diagnosed subjective impairment mild impairment.

Language: Английский

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The hippocampus associated GABAergic neural network impairment in early-stage of Alzheimer's disease

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 86, P. 101865 - 101865

Published: Jan. 28, 2023

Language: Английский

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