ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease

Acta Neuropathologica Communications, Год журнала: 2023, Номер 11(1)

Опубликована: Дек. 13, 2023

Abstract In sporadic Alzheimer’s disease (sAD) specific regions, layers and neurons accumulate hyperphosphorylated Tau (pTau) degenerate early while others remain unaffected even in advanced disease. ApoER2-Dab1 signaling suppresses phosphorylation as part of a four-arm pathway that regulates lipoprotein internalization the integrity actin, microtubules, synapses; however, role this sAD pathogenesis is not fully understood. We previously showed multiple components including ApoE, Reelin, ApoER2, Dab1, pP85α Tyr607 , pLIMK1 Thr508 pTau Ser202/Thr205 pPSD95 Thr19 together within entorhinal-hippocampal terminal zones sAD, proposed unifying hypothesis wherein disruption underlies aspects pathogenesis. However, it yet known whether can help explain origin(s) progression pathology sAD. present study, we applied situ hybridization immunohistochemistry (IHC) to characterize ApoER2 expression accumulation five regions develop 64 rapidly autopsied cases spanning clinicopathological spectrum found (1) these selectively vulnerable neuron populations strongly express ApoER2; (2) representing all four arms abnormal neuritic plaques mild cognitive impairment (MCI) correlate with histological deficits. Multiplex-IHC revealed many same ApoER2-expressing immediate vicinity ApoE/ApoJ-enriched extracellular plaques. Collective findings reveal only one neuroanatomical sites earliest stages provide support for concept drives pTau-associated neurodegeneration human

Язык: Английский

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The Primary Cilia are Associated with the Axon Initial Segment in Neurons

Advanced Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 13, 2025

Abstract The primary cilia serve as pivotal mediators of environmental signals and play crucial roles in neuronal responses. Disruption ciliary function has been implicated circuit disorders aberrant excitability. However, the precise mechanisms remain elusive. To study link between excitability, manipulation somatostatin receptor 3 (SSTR3) is investigated, an example how alterations signaling may affect activity. It found that SSTR3 expression perturbed not only morphology but also disrupted cascades. Genetic deletion resulted spatial memory synaptic plasticity. axon initial segment (AIS) a specialized region where action potentials are initiated. Interestingly, loss led to decrease Akt‐dependent cyclic AMP‐response element binding protein (CREB)‐mediated transcription at AIS, specifically downregulating AIS master organizer adaptor ankyrin G (AnkG) expression. In addition, other proteins serotonin 6 (5‐HT6R)and intraflagellar transport 88 (IFT88) induced length changes AIS. findings elucidate specific interaction providing insight into impact on excitability integrity.

Язык: Английский

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The dynamic axon initial segment: From neuronal polarity to network homeostasis

Neuron, Год журнала: 2025, Номер 113(5), С. 649 - 669

Опубликована: Фев. 12, 2025

The axon initial segment (AIS) is a highly specialized compartment in neurons that resides between axonal and somatodendritic domains. localization of the AIS proximal part essential for its two major functions: generating modulating action potentials maintaining neuron polarity. Recent findings revealed incredibly stable generated from dynamic components can undergo extensive structural functional changes response to alterations activity levels. These activity-dependent structure function have profound consequences neuronal functioning, plasticity has emerged as key regulator network homeostasis. This review highlights functions AIS, architecture, how organization remodeling are influenced by developmental both acute chronic adaptations. It also discusses mechanisms underlying these processes explores dysregulated may contribute brain disorders.

Язык: Английский

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Contribution of Axon Initial Segment Structure and Channels to Brain Pathology

Cells, Год журнала: 2023, Номер 12(8), С. 1210 - 1210

Опубликована: Апрель 21, 2023

Brain channelopathies are a group of neurological disorders that result from genetic mutations affecting ion channels in the brain. Ion specialized proteins play crucial role electrical activity nerve cells by controlling flow ions such as sodium, potassium, and calcium. When these not functioning properly, they can cause wide range symptoms seizures, movement disorders, cognitive impairment. In this context, axon initial segment (AIS) is site action potential initiation most neurons. This region characterized high density voltage-gated sodium (VGSCs), which responsible for rapid depolarization occurs when neuron stimulated. The AIS also enriched other channels, potassium shaping waveform determining firing frequency neuron. addition to contains complex cytoskeletal structure helps anchor place regulate their function. Therefore, alterations scaffold proteins, cytoskeleton may brain necessarily associated with channel mutations. review will focus on how AISs structure, plasticity, composition generate changes potentials neuronal dysfunction leading diseases. function be consequence mutations, but due ligand-activated receptors structural membrane support channels.

Язык: Английский

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Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons

Molecular Psychiatry, Год журнала: 2022, Номер 28(2), С. 746 - 758

Опубликована: Окт. 7, 2022

Язык: Английский

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Alzheimer’s disease: an axonal injury disease?

Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Окт. 19, 2023

Alzheimer’s disease (AD) is the primary cause of dementia and anticipated to impose a substantial economic burden in future. Over significant period, widely accepted amyloid cascade hypothesis has guided research efforts, recent FDA approval an anti- amyloid-beta (Aβ) protofibrils antibody, believed decelerate AD progression, further solidified its significance. However, excessive emphasis placed on overshadowed physiological nature Aβ tau proteins within axons. Axons, specialized neuronal structures, sustain damage during early stages AD, exerting pivotal influence progression. In this review, we present comprehensive summary relationship between axonal pathology, amalgamating roles proteins, along with impact risk genes such as APOE TREM2. Furthermore, underscore exceptional significance context AD.

Язык: Английский

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Modifying Alzheimer’s disease pathophysiology with photobiomodulation: model, evidence, and future with EEG-guided intervention

Frontiers in Neurology, Год журнала: 2024, Номер 15

Опубликована: Авг. 23, 2024

This manuscript outlines a model of Alzheimer’s Disease (AD) pathophysiology in progressive layers, from its genesis to the development biomarkers and then symptom expression. Genetic predispositions are major factor that leads mitochondrial dysfunction subsequent amyloid tau protein accumulation, which have been identified as hallmarks AD. Extending beyond these accumulations, we explore broader spectrum pathophysiological aspects, including blood–brain barrier, blood flow, vascular health, gut-brain microbiodata, glymphatic metabolic syndrome, energy deficit, oxidative stress, calcium overload, inflammation, neuronal synaptic loss, brain matter atrophy, reduced growth factors. Photobiomodulation (PBM), delivers near-infrared light selected regions using portable devices, is introduced therapeutic approach. PBM has potential address each with data provided by various studies. They provide mechanistic support for largely small published clinical studies demonstrate improvements memory cognition. inform PBM’s treat AD pending validation large randomized controlled The presentation network waveform changes on electroencephalography (EEG) opportunity use guide application parameters improve outcomes. These include wavelength, power density, treatment duration, LED positioning, pulse frequency. Pulsing at specific frequencies found influence expression waveforms modifications networks. stems modulation cellular structures revealed recent findings an EEG-based artificial intelligence personalize through EEG feedback.

Язык: Английский

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Spatiotemporal insights of APP function

Current Opinion in Neurobiology, Год журнала: 2023, Номер 82, С. 102754 - 102754

Опубликована: Авг. 3, 2023

The amyloid-β precursor protein (APP) is a ubiquitous with strong genetic link to Alzheimer's disease. Although the was identified more than forty years ago, its physiological function still unclear. In recent years, advances in technology have allowed researchers tackle APP functions greater depth. this review, we discuss latest research pertaining from development aging. We also address different roles that could play specific types of cells central and peripheral nervous system other organs body. argue that, until fully identify space time, will be missing important pieces puzzle solve pathological implication disease beyond.

Язык: Английский

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The amyloid-β peptide: Guilty as charged?

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2023, Номер 1870(2), С. 166945 - 166945

Опубликована: Ноя. 5, 2023

Язык: Английский

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Alterations in the axon initial segment plasticity is involved in early pathogenesis in Alzheimer's disease

MedComm, Год журнала: 2024, Номер 5(11)

Опубликована: Окт. 14, 2024

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by early presence of amyloid-β (Aβ) and hyperphosphorylated tau. Identifying neuropathological changes preceding cognitive decline crucial for intervention. Axon initial segment (AIS) maintains orderly structure axon responsible initiating action potentials (APs). To investigate role AIS in stages AD pathogenesis, we focused on alterations neurons from APP/PS1 mouse models harboring familial mutations. length electrophysiological properties were assessed using immunostaining patch-clamp techniques. The expression function ankyrin G (AnkG) isoforms evaluated western blot rescue experiments. We observed a significant shortening mice, which correlated with impaired potential propagation. Furthermore, decrease 480 kDa isoform AnkG was observed. Rescue this restored plasticity improved long-term potentiation neurons. Our study implicates dysregulation as events AD. restoration integrity presents therapeutic strategy AD, underscoring importance targeting stability diseases.

Язык: Английский

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