Selectively vulnerable deep cortical layer 5/6 fast-spiking interneurons in Alzheimer’s disease models in vivo DOI Creative Commons
Amalia Papanikolaou, David Graykowski, Byung Il Lee

et al.

Neuron, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Alzheimer's disease (AD) is initiated by amyloid-beta (Aβ) accumulation in the neocortex; however, cortical layers and neuronal cell types first susceptible to Aβ remain unknown. Using vivo two-photon Ca2+ imaging visual cortex of AD mouse models, we found that layer 5 neurons displayed abnormally prolonged transients before substantial plaque formation. Neuropixels recordings revealed these abnormal were associated with reduced spiking impaired tuning parvalbumin (PV)-positive fast-spiking interneurons (FSIs) 5/6, whereas PV-FSIs superficial remained unaffected. These dysfunctions occurred alongside a deep-layer-specific reduction pentraxin 2 (NPTX2) within excitatory neurons, decreased GluA4 PV-FSIs, fewer synapses onto PV-FSIs. Notably, NPTX2 overexpression increased input 5/6 rectified their activity. Thus, our findings reveal an early selective impairment deep models identify deep-layer as therapeutic targets.

Language: Английский

Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology DOI Creative Commons
Prateek Kumar, Annie M Goettemoeller, Claudia Espinosa‐García

et al.

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

Published: April 1, 2024

Abstract Dysfunction in fast-spiking parvalbumin interneurons (PV-INs) may represent an early pathophysiological perturbation Alzheimer’s Disease (AD). Defining proteomic alterations PV-INs can provide key biological and translationally-relevant insights. We used cell-type-specific in-vivo biotinylation of proteins (CIBOP) coupled with mass spectrometry to obtain native-state PV-IN proteomes. signatures include high metabolic translational activity, over-representation AD-risk cognitive resilience-related proteins. In bulk proteomes, were associated decline humans, progressive neuropathology humans the 5xFAD mouse model Aβ pathology. CIBOP stages pathology revealed increased mitochondria metabolism, synaptic cytoskeletal disruption decreased mTOR signaling, not apparent whole-brain Furthermore, we demonstrated pre-synaptic defects PV-to-excitatory neurotransmission, validating our findings. Overall, this study present proteomes PV-INs, revealing molecular insights into their unique roles resiliency AD pathogenesis.

Language: Английский

Citations

22
Amyloid-associated hyperconnectivity drives tau spread across connected brain regions in Alzheimer’s disease DOI Open Access
Sebastian Niclas Roemer,

Franziska Wagner,

Lisa Evangelista

et al.

Science Translational Medicine, Journal Year: 2025, Volume and Issue: 17(782)

Published: Jan. 22, 2025

In Alzheimer’s disease (AD), amyloid-β (Aβ) triggers the aggregation and spreading of tau pathology, which drives neurodegeneration cognitive decline. However, pathophysiological link between Aβ remains unclear, hinders therapeutic efforts to attenuate Aβ-related accumulation. has been found trigger neuronal hyperactivity hyperconnectivity, preclinical research shown that spreads across connected neurons in an activity-dependent manner. Here, we hypothesized hypersynchronicity, resulting functional connectivity increases, constitute a crucial mechanism by facilitates pathology. By combining positron emission tomography (PET), resting-state magnetic resonance imaging, longitudinal tau-PET 69 cognitively normal amyloid-negative controls 140 amyloid-positive patients covering AD spectrum, confirmed induces hyperconnectivity temporal lobe epicenters posterior brain regions are vulnerable accumulation AD. This was replicated independent sample 55 345 individuals with low cortical uptake, suggesting emergence precedes neocortical . Last, using mediation analysis, these increases typical tau-vulnerable mediated effect on faster accumulation, unveiling increased as potential causal two hallmark pathologies. Together, findings suggest promotes eliciting targeting may

Language: Английский

Citations

5
The metabolic costs of cognition DOI
Sharna D. Jamadar, Anna Behler, Hamish A Deery

et al.

Trends in Cognitive Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

2
Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease DOI Creative Commons
Rikesh M. Rajani, Robert Ellingford,

Mariam Hellmuth

et al.

PLoS Biology, Journal Year: 2024, Volume and Issue: 22(7), P. e3002727 - e3002727

Published: July 23, 2024

Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer's disease (AD), but the underlying assumption that neurons are main source pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating oligodendrocytes an important human brain and play a key role promoting abnormal neuronal hyperactivity AD knock-in mouse model. We show selectively suppressing oligodendrocyte production improves pathology restores function model vivo. Our findings suggest targeting could promising therapeutic strategy for AD.

Language: Английский

Citations

14
Sleep and Neurodegeneration: Examining Potential Physiological Mechanisms DOI
Brice V. McConnell, Yulin Deng, Brendan P. Lucey

et al.

Current Sleep Medicine Reports, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 3, 2025

Language: Английский

Citations

1
Heterogeneous brain abnormalities in subjective cognitive decline converge on a common network and their transcriptional signature DOI Creative Commons
Huan Lan, Wei Liu, Chao Zuo

et al.

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(3)

Published: March 1, 2025

Abstract INTRODUCTION Subjective cognitive decline (SCD) is increasingly recognized as closely related to future Alzheimer's disease (AD). Numerous neuroimaging findings in SCD are inconsistent. We tested whether the various localize a common brain network. METHODS Using novel coordinate network mapping approach, we delineated damage networks that were functionally connected reported findings. then decoded these using microscale transcriptomic and chemo‐architectures psychological processes. RESULTS enrolled 45 studies comprising 2453 patients 3017 healthy controls. The identified largely localized somatosensory (SMN) default mode (DMN). Both robust perturbations of analyzed parameters an independent validation dataset. Neurobiology correlation analyses some key biological pathways neurotransmitters linked networks. DISCUSSION Our reconcile heterogeneous abnormalities provide richer neurobiological underpinning, which has implications for understanding with SCD. Highlights on reconciled framework. SCD‐related functional involves changes DMN, while structural mainly primary sensory areas. genes predominantly enriched processes synaptic structure, calcium ion binding, cellular metabolism. An ALE meta‐analysis was conducted comparison.

Language: Английский

Citations

1
Association of Seizure Foci and Location of Tau and Amyloid Deposition and Brain Atrophy in Patients With Alzheimer Disease and Seizures DOI
Alice Lam, Emma G. Thibault,

Danielle V. Mayblyum

et al.

Neurology, Journal Year: 2024, Volume and Issue: 103(9)

Published: Sept. 27, 2024

Alzheimer disease (AD) is associated with a 2 to 3-fold increased risk of developing late-onset focal epilepsy, yet it remains unclear how development epilepsy in AD related pathology. The objective this study was examine spatial relationships between the epileptogenic zone and tau deposition, amyloid brain atrophy individuals who developed late-onset, otherwise unexplained epilepsy. We hypothesized that if network hyperexcitability mechanistically linked pathology, then there would be deposition within hemisphere.

Language: Английский

Citations

8
Epileptic activity on foramen ovale electrodes is associated with sleep and tau pathology in Alzheimer’s disease DOI Creative Commons
Astrid Devulder, Greet Vanderlinden,

Leen Van Langenhoven

et al.

Brain, Journal Year: 2024, Volume and Issue: 148(2), P. 506 - 520

Published: July 10, 2024

Both sleep alterations and epileptiform activity are associated with the accumulation of amyloid-β tau pathology currently investigated for potential therapeutic interventions in Alzheimer's disease. However, a bidirectional intertwining relationship between neuronal hyperexcitability might modulate effects disease on corresponding associations. To investigate this, we performed multiple day simultaneous foramen ovale (FO) plus scalp EEG polysomnography recordings acquired 18F-MK6240 PET-MR three patients prodromal stage two mild moderate dementia due to disease, respectively. As an eligibility criterion present study, subjects either had history recent seizure (n = 2) or subclinical (SEA) previous taken research context 3). The standard uptake value ratio (SUVR) asymmetry index (AI) were calculated priori-defined volumes interest. Linear mixed-effects models used study associations interictal discharges (IEDs), parameters SUVR. Epileptiform was bilateral but asymmetrically FO electrodes all ≥95% IEDs not visible EEG. In one patient, focal seizures detected electrodes, both without visual correlate. We observed lateralized periodic discharges, brief potentially ictal rhythmic delta four patients. Unlike EEG, intracranial showed lateralization activity. Although amount SUVR binding different interest, there congruent towards most epileptic hemisphere mesial (P 0.007) lateral temporal cortex 0.006). abundant during slow wave (SWS) (92/h) non-REM 2 (N2, 81/h), followed by 1 (N1, 33/h) least frequent wakefulness (17/h) REM (9/h). extent reflected relative time each spent [REM% 0.415), N1% 0.668), N2% 0.442), SWS% 0.988)], arousal 0.317), apnoea-hypopnoea 0.846) oxygen desaturation 0.746). Together, our observations suggest multi-directional interaction sleep,

Language: Английский

Citations

7
Personalized whole-brain neural mass models reveal combined Aβ and tau hyperexcitable influences in Alzheimer’s disease DOI Creative Commons
Lazaro M. Sanchez-Rodriguez, Gleb Bezgin, Félix Carbonell

et al.

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: May 4, 2024

Abstract Neuronal dysfunction and cognitive deterioration in Alzheimer’s disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence humans remains scarce, requiring improved non-invasive techniques integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators incorporating resting-state functional MRI, amyloid-β (Aβ) tau-PET from 132 individuals the spectrum to evaluate direct impact of toxic protein deposition neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ tau effects impairment excitability increases with progression. The data-derived values strongly predict clinically relevant plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show hallmark electrophysiological alterations (theta band activity enhancement alpha reductions) which occur Aβ-positivity after limbic involvement. Microglial activation influences less definitive, potentially due neuroimaging limitations mapping neuroprotective vs detrimental phenotypes. Mechanistic brain can further clarify intricate neurodegenerative processes accelerate preventive/treatment interventions.

Language: Английский

Citations

6
Cerebral hyperactivation across the Alzheimer’s disease pathological cascade DOI Creative Commons
Nick Corriveau‐Lecavalier, Jenna N. Adams, Larissa Fischer

et al.

Brain Communications, Journal Year: 2024, Volume and Issue: 6(6)

Published: Jan. 1, 2024

Neuronal dysfunction in specific brain regions or across distributed networks is a known feature of Alzheimer's disease. An often reported finding the early stage disease presence increased functional MRI (fMRI) blood oxygenation level-dependent signal under task conditions relative to cognitively normal controls, phenomenon as 'hyperactivation'. However, research past decades yielded complex, sometimes conflicting results. The magnitude and topology fMRI hyperactivation patterns have been found vary preclinical clinical spectrum disease, including concomitant 'hypoactivation' some cases. These incongruences are likely due range factors, at which cohort examined, areas studied paradigm utilized evoke these abnormalities. Additionally, perennial question pertains nature context Some propose it reflects compensatory mechanisms sustain cognitive performance, while others suggest linked pathological disruption highly regulated homeostatic cycle that contributes to, even drives, progression. Providing coherent narrative for empirical conceptual discrepancies paramount develop models, understand synergy between cascade tailor effective interventions. We first provide comprehensive overview changes spanning course from ageing then highlight evidence supporting close relationship

Language: Английский

Citations

6