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

Fibre density and cross-section associate with hallmark pathology in early Alzheimer’s disease DOI Creative Commons
Greet Vanderlinden, Ahmed Radwan, Daan Christiaens

et al.

Alzheimer s Research & Therapy, Journal Year: 2025, Volume and Issue: 17(1)

Published: April 5, 2025

Language: Английский

Citations

0
Differential effects of aging, Alzheimer's pathology, and APOE4 on longitudinal functional connectivity and episodic memory in older adults DOI Creative Commons
Larissa Fischer, Jenna N. Adams, Eóin N. Molloy

et al.

Alzheimer s Research & Therapy, Journal Year: 2025, Volume and Issue: 17(1)

Published: April 25, 2025

Abstract Background Both aging and Alzheimer's disease (AD) affect brain networks, with early disruptions occurring in regions involved episodic memory. Few studies have, however, focused on distinguishing region-specific effects of AD-biomarker negative “normal” amyloid- tau pathology functional connectivity. Further, longitudinal combining imaging, biomarkers, cognition are rare. Methods We assessed resting-state connectivity (rsFC) strength graph measures the memory network including medial temporal lobe (MTL), posteromedial cortex (PMC), prefrontal alongside over two years. For this preregistered study, we included 100 older adults who were tau-negative using CSF PET measurements to investigate aging, 70 had data available changes related AD pathology. All participants cognitively unimpaired from PREVENT-AD cohort. used region interest (ROI)-to-ROI bivariate correlations, analysis, multiple regression models. Results In sample, rsFC within PMC, between parahippocampal inferomedial precuneus, posterior hippocampus precuneus decreased time. Additionally, observed a decrease global efficiency. there was steeper efficiency higher baseline age particularly parahippocampal-gyrus regions. lower PMC associated poorer performance. sample data, increase anterior superior Higher MTL-PMC differentially trajectories depending APOE4 genotype. Conclusions Our findings suggest differential Hypoconnectivity cognitive decline. hyperconnectivity decline carriers. Future should more diverse samples, nonetheless, our approach allowed us identify pathology, enhancing cross-sectional research. Hyperconnectivity has been proposed as mechanism before, now contribute specific connections focus future Graphical A ) “Normal aging” tau- biomarker status characterized by strength. B Cognitively Alzheimer’s at (measured via cerebrospinal fluid) exhibited

Language: Английский

Citations

0
Modeling functional connectivity with learning and memory in a mouse model of Alzheimer's disease DOI Creative Commons

Lindsay Fadel,

Elizabeth Hipskind, Steen E. Pedersen

et al.

Frontiers in Neuroimaging, Journal Year: 2025, Volume and Issue: 4

Published: April 25, 2025

Introduction Functional connectivity (FC) is a metric of how different brain regions interact with each other. Although there have been some studies correlating learning and memory FC, not yet been, to date, that use machine (ML) explain FC changes can be used behavior only in healthy mice, but also mouse models Alzheimer's Disease (AD). Here, we investigated their relationship model AD across disease progression. Methods We assessed the APP/PS1 wild-type controls at 3-, 6-, 10-months age. Using resting state functional magnetic resonance imaging (rs-fMRI) awake, unanesthetized between 30 regions. ML were then define interactions neuroimaging readouts performance. Results In identified pattern hyperconnectivity all three time points, 47 hyperconnected 3 months, 46 6 84 10 months. Notably, observed Default Mode Network, exhibiting loss over time. Modeling revealed connections support performance differ 6- 10-month groups. Discussion These show potential for early detection by identifying patterns associated cognitive decline. Additionally, may provide means begin understand translates into

Language: Английский

Citations

0
Calbindin-D28k deficiency mediates tau-driven hippocampal hyperexcitement and cognitive impairment DOI
Yang Gao,

Xiaoqing Tao,

Yuying Wang

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

Abstract Background Medial temporal lobe hyperexcitation or seizures originating from hippocampus are frequently observed in Alzheimer's disease (AD) patients, contributing to accelerated cognitive decline. Given the hippocampus's role as an early vulnerable area of tau pathology, a hallmark AD, mechanisms by which abnormal aggregation promotes epilepsy (TLE) remain poorly understood. Methods We investigated and AD-like hippocampal neuronal using transgenic (Tg) tau-driven mice. Tau on intracellular calcium dynamics was assessed imaging. Neuronal/network hyperexcitability seizure susceptibility were evaluated through patch-clamp electrophysiology, 18F-FDG PET/CT, optogenetic induction. A tetracycline-controlled (tet-on) system Tg hTau368 mice enabled spatiotemporal induction pathology investigate interactions with calbindin-D28k (CB) synaptic proteins. Adeno-associated virus (AAV)-mediated CB supplementation CA1 dentate gyrus (DG) excitatory neurons tested for rescuing deficits. Finally, relationship between progress analyzed AD public database. Results accumulation CA1/DG CaMKII-positive reduced expression disrupted homeostasis. This dysregulation heightened excitability, diminished protein levels, increased impairment. AAV-driven restoration attenuated both In brain associated deterioration advanced stages. Conclusions drives CB-dependent hyperexcitation. These results establish potential mechanistic link tauopathy TLE pathogenesis providing promising therapeutic target mitigating risk related decline AD.

Language: Английский

Citations

0
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

Citations

0