Accurate classification of major brain cell types using in vivo imaging and neural network processing DOI Creative Commons
Amrita Gupta, Livia Asan,

Jennifer John

et al.

PLoS Biology, Journal Year: 2023, Volume and Issue: 21(11), P. e3002357 - e3002357

Published: Nov. 9, 2023

Comprehensive analysis of tissue cell type composition using microscopic techniques has primarily been confined to ex vivo approaches. Here, we introduce NuCLear ( Nu cleus-instructed c omposition deep lear ning), an approach combining in two-photon imaging histone 2B-eGFP-labeled nuclei with subsequent learning-based identification types from structural features the respective nuclei. Using NuCLear, were able classify almost all cells per volume secondary motor cortex mouse brain (0.25 mm 3 containing approximately 25,000 cells) and identify their position 3D space a noninvasive manner only single label throughout multiple sessions. Twelve weeks after baseline, numbers did not change yet astrocytic significantly decreased size. opens window study changes relative density location different brains individual mice over extended time periods, enabling comprehensive studies physiological pathophysiological conditions.

Language: Английский

Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression DOI Creative Commons
S. Meftah, Jian Gan

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

Citations

74
Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps and conundrums DOI
Anita Kamondi, Madeleine Grigg‐Damberger, Wolfgang Löscher

et al.

Nature Reviews Neurology, Journal Year: 2024, Volume and Issue: 20(3), P. 162 - 182

Published: Feb. 14, 2024

Language: Английский

Citations

33
Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease DOI Creative Commons
Maria Calvo‐Rodriguez, Elizabeth K. Kharitonova,

Austin Snyder

et al.

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 18, 2024

Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration Alzheimer's disease (AD). Damaged mitochondria are one of main sources reactive oxygen species and accumulate Aβ plaque-associated dystrophic neurites AD brain. Although causes neuronal vitro, this has never been directly observed vivo living mouse Here, we tested for first time whether plaques soluble oligomers induce mitochondrial surrounding neurons vivo, neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants.

Language: Английский

Citations

32
Sensory processing deficits and related cortical pathological changes in Alzheimer’s disease DOI Creative Commons
Nicole K. Zhang,

Selena K. Zhang,

Li I. Zhang

et al.

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

Published: Aug. 15, 2023

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder primarily affecting cognitive functions. However, sensory deficits in AD start to draw attention due their high prevalence and early onsets which suggest that they could potentially serve as diagnostic biomarkers even contribute the progression. This literature review examines cortical pathological changes observed visual, auditory, olfactory, somatosensory systems patients, well various animal models. Sensory may emerge at stages of AD, or precede decline, accompanied by including amyloid-beta deposition, tauopathy, gliosis, alterations neuronal excitability, synaptic inputs, functional plasticity. Notably, these are more pronounced association areas superficial layers, explain relative preservation basic functions but display higher We propose impairment progression establish cyclical relationship mutually perpetuates each condition. highlights significance with without emphasizes need for further research develop reliable detection intervention through systems.

Language: Английский

Citations

17
APOE3-R136S Mutation Confers Resilience Against Tau Pathology via cGAS-STING-IFN Inhibition DOI
Sarah Naguib, Eileen Ruth S. Torres, Chloe Lopez-Lee

et al.

Published: Jan. 1, 2024

The Christchurch mutation (R136S) on the APOE3 (E3S/S) gene is associated with low tau pathology and slowdown of cognitive decline despite causal PSEN1 high levels amyloid beta in carrier1. However, molecular effects enabling E3S/S to confer protection remain unclear. Here, we replaced mouse Apoe wild-type human E3 or a tauopathy background. R136S markedly mitigated load protected against tau-induced synaptic loss, myelin spatial learning. Additionally, reduced microglial interferon response both vivo vitro, suppressing cGAS-STING activation. Treating mice carrying cGAS inhibitor loss induced similar transcriptomic alterations those by across brain cell types. Thus, cGAS-STING-IFN inhibition recapitulates protective tauopathy.

Language: Английский

Citations

8
Interictal epileptiform discharges affect memory in an Alzheimer’s disease mouse model DOI Creative Commons
Marisol Soula, Anna Maslarova, Ryan E. Harvey

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(34)

Published: Aug. 17, 2023

Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but also present other neurological diseases, such as Alzheimer's disease (AD). Understanding the role IEDs have on hippocampal circuit is important for our understanding of cognitive deficits seen and AD. We characterize compare human from microwire recording with those AD transgenic mice implanted multilayer silicon probes. Both local field potential features firing patterns pyramidal cells interneurons were similar mouse human. found that emerged CA3-1 circuits, they recruited silenced interneurons, followed by post-IED suppression. suppressed incidence altered properties physiological sharp-wave ripples, their properties, interfered replay place sequences a maze. In addition, inversely correlated daily memory performance. Together, work implies may common epilepsy-independent phenomenon neurodegenerative diseases perturbs hippocampal-cortical communication interferes memory.

Language: Английский

Citations

15
Neuroinflammation increases oxygen extraction in a mouse model of Alzheimer’s disease DOI Creative Commons
Chang Liu, Alfredo Cárdenas‐Rivera,

Shayna Teitelbaum

et al.

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: April 10, 2024

Neuroinflammation, impaired metabolism, and hypoperfusion are fundamental pathological hallmarks of early Alzheimer's disease (AD). Numerous studies have asserted a close association between neuroinflammation disrupted cerebral energetics. During AD progression other neurodegenerative disorders, persistent state chronic reportedly exacerbates cytotoxicity potentiates neuronal death. Here, we assessed the impact neuroinflammatory challenge on metabolic demand microvascular hemodynamics in somatosensory cortex an mouse model.

Language: Английский

Citations

5
A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity‐dependent synaptic and microglial transcriptomic changes in a late‐stage Alzheimer's mouse model DOI Creative Commons

Amira Latif‐Hernandez,

Tao Yang, Robert R. Butler

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(7), P. 4434 - 4460

Published: May 23, 2024

Abstract INTRODUCTION Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C could reduce Alzheimer's disease (AD)‐related degenerative signaling, memory loss, dysfunction. METHODS PTX‐BD10‐2 (BD10‐2), a small molecule partial agonist, was orally administered to aged London/Swedish‐APP mutant mice (APP L/S ) wild‐type controls. Effects on hippocampal long‐term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, RNA sequencing. RESULTS In APP mice, BD10‐2 treatment improved LTP deficits. This accompanied normalized phosphorylation of protein (Akt), calcium‐calmodulin–dependent II (CaMKII), AMPA‐type glutamate receptors containing the subunit GluA1; enhanced activity‐dependent recruitment proteins; increased excitatory synapse number. also had potentially favorable effects LTP‐dependent complement pathway gene transcription. DISCUSSION prevented /Aβ‐associated deficits, reduced abnormalities in synapse‐related transcription genes, bolstered transcriptional changes associated microglial immune response. Highlights Small modulation tropomyosin restores behavior an (AD) model. Modulation TrkB TrkC regulates are candidate targets for translational therapeutics. Electrophysiology combined transcriptomics elucidates restoration. identifies neuron microglia AD‐relevant human‐mouse co‐expression modules.

Language: Английский

Citations

5
Cognitive integrity in Non‐Demented Individuals with Alzheimer's Neuropathology is associated with preservation and remodeling of dendritic spines DOI Creative Commons

Jutatip Guptarak,

Pietro Scaduto,

Batbayar Tumurbaatar

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(7), P. 4677 - 4691

Published: June 3, 2024

Individuals referred to as Non-Demented with Alzheimer's Neuropathology (NDAN) exhibit cognitive resilience despite presenting disease (AD) histopathological signs. Investigating the mechanisms behind this may unveil crucial insights into AD resistance.

Language: Английский

Citations

5
APOE3-R136Smutation confers resilience against tau pathology via cGAS-STING-IFN inhibition DOI Creative Commons

Sarah Naguib,

Eileen Ruth S. Torres, Chloe Lopez-Lee

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 28, 2024

Summary The Christchurch mutation (R136S) on the APOE3 ( E3 S/S ) gene is associated with low tau pathology and slowdown of cognitive decline despite causal PSEN1 high levels amyloid beta in carrier 1 . However, molecular effects enabling to confer protection remain unclear. Here, we replaced mouse Apoe wild-type human or a tauopathy background. R136S markedly mitigated load protected against tau-induced synaptic loss, myelin spatial learning. Additionally, reduced microglial interferon response both vivo vitro , suppressing cGAS-STING activation. Treating mice carrying cGAS inhibitor loss induced similar transcriptomic alterations those by across brain cell types. Thus, cGAS-STING-IFN inhibition recapitulates protective tauopathy. One-sentence summary enhances resistance tau-related disease processes downregulating signaling pathway.

Language: Английский

Citations

4