Astrocyte–neuron interplay is critical for Alzheimer's disease pathogenesis and is rescued by TRPA1 channel blockade DOI Open Access
Adrien Paumier, Sylvie Boisseau, Muriel R. Jacquier‐Sarlin

et al.

Brain, Journal Year: 2021, Volume and Issue: 145(1), P. 388 - 405

Published: July 22, 2021

The sequence of cellular dysfunctions in preclinical Alzheimer's disease must be understood if we are to plot new therapeutic routes. Hippocampal neuronal hyperactivity is one the earliest events occurring during stages both humans and mouse models. most common hypothesis describes amyloid-β accumulation as triggering factor but effects this cascade leading cognitive decline remain unclear. In mice, previously showed that amyloid-β-dependent TRPA1 channel activation triggers hippocampal astrocyte hyperactivity, subsequently inducing nearby neurons. work, investigated potential protection against progression provided by early chronic pharmacological inhibition channel. A specific inhibitor (HC030031) was administered intraperitoneally from onset overproduction APP/PS1-21 model disease. Short-, medium- long-term blockade were characterized on at functional (astrocytic activity), structural, biochemical behavioural levels. Our results revealed first observable disruptions transgenic used correspond aberrant neuron hyperactivity. We normalizes astrocytic activity, avoids perisynaptic process withdrawal, prevents dysfunction preserves structural synaptic integrity. These protective preserved spatial working memory model. toxic effect astrocytes triggered pivotal progression. irreversible dysfunction, making a target promote neuroprotection.

Language: Английский

Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review DOI Creative Commons
Danko Jeremic, Lydia Jiménez‐Díaz, Juan D. Navarro‐López

et al.

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 72, P. 101496 - 101496

Published: Oct. 22, 2021

Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.

Language: Английский

Citations

220
Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls DOI Creative Commons
Swagata Ghatak,

Nima Dolatabadi,

Dorit Trudler

et al.

eLife, Journal Year: 2019, Volume and Issue: 8

Published: Nov. 29, 2019

Human Alzheimer’s disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, underlying mechanism for this excessive excitability remains incompletely understood. To investigate basis hyperactivity, we performed electrophysiological immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures cerebral organoids bearing AD-related mutations in presenilin-1 or amyloid precursor protein vs. isogenic gene corrected controls. In neurons/organoids, found increased excitatory bursting activity, which could be explained part a decrease neurite length. neurons also displayed sodium current density decreased inhibitory activity. Our findings establish as relevant model early pathophysiology provide mechanistic insight into observed

Language: Английский

Citations

186
Sleep and synaptic down‐selection DOI
Giulio Tononi, Chiara Cirelli

European Journal of Neuroscience, Journal Year: 2019, Volume and Issue: 51(1), P. 413 - 421

Published: Jan. 7, 2019

Abstract The synaptic homeostasis hypothesis (SHY) proposes that sleep is an essential process needed by the brain to maintain total amount of strength under control. SHY predicts end a waking day connections many neural circuits undergo net increase in due ongoing learning, which mainly mediated potentiation. Stronger synapses require more energy and supplies are prone saturation, creating need for renormalization. Such renormalization should occur during sleep, when disconnected from environment can be broadly reactivated off‐line systematic but specific down‐selection. In short, according price pay plasticity, avoid runaway potentiation, decreased signal‐to‐noise ratio, impaired learning saturation. this review, we briefly discuss rationale recent supportive ultrastructural evidence obtained our laboratory. We then examine studies other groups showing causal role cortical slow waves hippocampal sharp waves/ripples sleep‐dependent down‐selection activity strength. Finally, some molecular mechanisms could mediate weakening sleep.

Language: Английский

Citations

176
Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease DOI Creative Commons
Sara Hijazi, Tim S. Heistek, Philip Scheltens

et al.

Molecular Psychiatry, Journal Year: 2019, Volume and Issue: 25(12), P. 3380 - 3398

Published: Aug. 20, 2019

Abstract Neuronal network dysfunction is increasingly recognized as an early symptom in Alzheimer’s disease (AD) and may provide new entry points for diagnosis intervention. Here, we show that amyloid-beta-induced hyperexcitability of hippocampal inhibitory parvalbumin (PV) interneurons importantly contributes to neuronal memory impairment APP/PS1 mice, a mouse model increased amyloidosis. We demonstrate PV become hyperexcitable at ~16 weeks age, when no changes are observed yet the intrinsic properties pyramidal cells. This state coincides with transmission onto neurons deficits spatial learning memory. treatment aimed preventing from becoming sufficient restore interneuron wild-type levels, reduce input cells, rescue mice. Importantly, intervention restoring activity has long-term beneficial effects on activity, reduces amyloid plaque deposition, hallmark AD pathology. Taken together, these findings suggest hyperactivity might be clinically relevant decline delaying progression.

Language: Английский

Citations

168
Astrocyte energy and neurotransmitter metabolism in Alzheimer’s disease: Integration of the glutamate/GABA-glutamine cycle DOI
Jens V. Andersen, Arne Schousboe, Alexei Verkhratsky

et al.

Progress in Neurobiology, Journal Year: 2022, Volume and Issue: 217, P. 102331 - 102331

Published: July 21, 2022

Language: Английский

Citations

157
Targeting Homeostatic Synaptic Plasticity for Treatment of Mood Disorders DOI Creative Commons
Ege T. Kavalali, Lisa M. Monteggia

Neuron, Journal Year: 2020, Volume and Issue: 106(5), P. 715 - 726

Published: June 1, 2020

Language: Английский

Citations

148
Neuronal excitation/inhibition imbalance: core element of a translational perspective on Alzheimer pathophysiology DOI Creative Commons
Fernando Maestú, Willem de Haan, Marc Aurel Busche

et al.

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 69, P. 101372 - 101372

Published: May 21, 2021

Our incomplete understanding of the link between Alzheimer's Disease pathology and symptomatology is a crucial obstacle for therapeutic success. Recently, translational studies have begun to connect dots protein alterations deposition, brain network dysfunction cognitive deficits. Disturbance neuronal activity, in particular an imbalance underlying excitation/inhibition (E/I), appears early AD, can be regarded as forming central structural dysfunction. While there are emerging (non-)pharmacological options influence this imbalance, complexity human dynamics has hindered identification optimal approach. We suggest that focusing on integration neurophysiological aspects AD at micro-, meso- macroscale, with support computational modeling, unite fundamental clinical knowledge, provide general framework, rational targets.

Language: Английский

Citations

148
Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease DOI Creative Commons
Sam Harris, Fred Wolf, Bart De Strooper

et al.

Neuron, Journal Year: 2020, Volume and Issue: 107(3), P. 417 - 435

Published: June 23, 2020

Language: Английский

Citations

142
Increased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease DOI Creative Commons
Julie C. Lauterborn, Pietro Scaduto, Conor D. Cox

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 10, 2021

Synaptic disturbances in excitatory to inhibitory (E/I) balance forebrain circuits are thought contribute the progression of Alzheimer's disease (AD) and dementia, although direct evidence for such imbalance humans is lacking. We assessed anatomical electrophysiological synaptic E/I ratios post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography microtransplantation membranes. Both approaches revealed significantly elevated AD, but not DS, versus controls. Gene expression studies an independent cohort also demonstrated as compared These findings provide a marked pro-excitatory perturbation cortex, region within default mode network that overly active disorder, support hypothesis imbalances disrupt cognition-related shifts cortical activity which intellectual decline AD.

Language: Английский

Citations

110
Glutamate and GABA in Microglia-Neuron Cross-Talk in Alzheimer’s Disease DOI Open Access
Grzegorz A. Czapski, Joanna B. Strosznajder

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(21), P. 11677 - 11677

Published: Oct. 28, 2021

The physiological balance between excitation and inhibition in the brain is significantly affected Alzheimer's disease (AD). Several neuroactive compounds their signaling pathways through various types of receptors are crucial homeostasis, among them glutamate γ-aminobutyric acid (GABA). Activation microglial regulates immunological response these cells, which AD could be neuroprotective or neurotoxic. novel research approaches revealed complexity function, including interplay with other cells during neuroinflammation brain. purpose this review to describe role several proteins multiple on microglia neurons, involvement a communication network that lead different metabolic loops cell death/survival. Our focused glutamatergic, GABAergic microglia-neuronal cross-talk neuroinflammation. Moreover, significance AD-related neurotoxic glutamate/GABA-mediated dialogue neurons was analyzed search targets neuroprotection, advanced pharmacological approaches.

Language: Английский

Citations

107