Astrocytes mediate the pro-cognitive value of α7nAChRs and of α7nAChR-targeting therapeutics

bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-19

The α7-nicotinic acetylcholine receptor (α7nAChR) has driven extensive research over the past three decades for its pro-cognitive potential. It is the leading druggable target for the cognitive deficits associated with schizophrenia and has motivated major pharmaceutical and clinical efforts to ameliorate similar impairments in other neurological disorders, such as Alzheimer's disease (AD). Yet, a systematic evaluation of the role played by α7nAChR in cognition, and its mechanistic underpinnings, is still lacking. Here we report that α7nAChRs on principal and inhibitory forebrain neurons are largely inconsequential to mouse behavior, including in domains that are most sensitive to schizophrenia-related cognitive impairments. By contrast, loss of α7nAChR from astrocytes produces profound behavioral alterations that are cognitive domain-specific, are time-of-day dependent, coincide with reduced levels of the N-methyl D-aspartate receptor (NMDAR) co-agonist D-serine, and are fully restored by D-serine supplementation. Further, an α7nAChR partial agonist previously evaluated in Phase III trials for cognitive enhancement in schizophrenia and AD fails to augment behavior in mice lacking astrocytic α7nAChRs. Together, these findings identify astrocytes and D-serine/NMDAR signaling as a central mechanism through which α7nAChR, a major drug target, promotes cognitive behavior.

Microglial STING is a central safeguard against neurological decline with age

Cell Reports · 2025-05-30 · 2 citations

Functional decline of the central nervous system (CNS) is driven by the breakdown of the blood-brain barrier (BBB) and attendant inflammation, all hallmarks of age-related neurodegeneration. Despite intense interest in how the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway impacts neurodegenerative processes in aging, its role in shaping these features of CNS fate during physiological aging remains unclear. Here, using physiologically aged mice, we uncovered an unexpected but vital role for STING in preserving CNS function. We find that STING deficiency exacerbates neurological decline through BBB breakdown, microhemorrhages, and neuromotor deficits. Furthermore, STING deficiency leads to an accrual of neuronal DNA damage and alters CNS proinflammatory, type I interferon, and senescence signatures. Cumulatively, these changes lead to a transformation in microglia phenotypes and transcriptomes. Finally, microglial-STING expression is sufficient to elicit protection against age-associated changes in the CNS and highlights the mechanistic basis for STING-dependent protective mechanisms within the aging brain.

Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knock in mouse model of Alzheimer’s disease

bioRxiv (Cold Spring Harbor Laboratory) · 2024-04-25 · 2 citations

Summary The disease’s trajectory of Alzheimer’s disease (AD) is associated with and worsened by hippocampal hyperexcitability. Here we show that during the asymptomatic stage in a knock in mouse model of Alzheimer’s disease (APP NL-G-F/NL-G-F ; APPKI), hippocampal hyperactivity occurs at the synaptic compartment, propagates to the soma and is manifesting at low frequencies of stimulation. We show that this aberrant excitability is associated with a deficient adenosine tone, an inhibitory neuromodulator, driven by reduced levels of CD39/73 enzymes, responsible for the extracellular ATP-to-adenosine conversion. Both pharmacologic (adenosine kinase inhibitor) and non-pharmacologic (ketogenic diet) restorations of the adenosine tone successfully normalize hippocampal neuronal activity. Our results demonstrated that neuronal hyperexcitability during the asymptomatic stage of a KI model of Alzheimer’s disease originated at the synaptic compartment and is associated with adenosine deficient tone. These results extend our comprehension of the hippocampal vulnerability associated with the asymptomatic stage of Alzheimer’s disease. Abstract Figure Synaptic hyperexcitability spreads to the soma and manifests at low frequencies of stimulation Synaptic hyperexcitability is associated with reduced adenosine tone in vitro and in vivo Reduced adenosine tone is driven by reduced ATP-to-adenosine extracellular conversion Restoration of adenosine tone successfully normalizes neuronal excitability in the AD model

Adenosine deficiency facilitates CA1 synaptic hyperexcitability in the presymptomatic phase of a knockin mouse model of Alzheimer disease

iScience · 2024-12-18 · 1 citations

; APPKI), hippocampal hyperactivity occurs at the synaptic compartment, propagates to the soma, and is manifesting at low frequencies of stimulation. We show that this aberrant excitability is associated with a deficient adenosine tone, an inhibitory neuromodulator, driven by reduced levels of CD39/73 enzymes, responsible for the extracellular ATP-to-adenosine conversion. Both pharmacologic (adenosine kinase inhibitor) and non-pharmacologic (ketogenic diet) restorations of the adenosine tone successfully normalize hippocampal neuronal activity. Our results demonstrated that neuronal hyperexcitability during the asymptomatic stage of a KI model of Alzheimer disease originated at the synaptic compartment and is associated with adenosine deficient tone. These results extend our comprehension of the hippocampal vulnerability associated with the asymptomatic stage of Alzheimer disease.

Astrocytic metabolic control of orexinergic activity in the lateral hypothalamus regulates sleep and wake architecture

bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-29 · 1 citations

ABSTRACT Neuronal activity undergoes significant changes during vigilance states, accompanied by an accommodation of energy demands. While the astrocyte-neuron lactate shuttle has shown that lactate is the primary energy substrate for sustaining neuronal activity in multiple brain regions, its role in regulating sleep/wake architecture is not fully understood. We manipulated the cell-specific expression of monocarboxylate transporters (MCTs), the major lactate transporters, to examine the involvement of astrocytic lactate supply in maintaining consolidated wakefulness. Our results demonstrate that reduced expression of MCT4 in astrocytes disrupts lactate supply to orexin neurons in the lateral hypothalamus (LH), impairing wakefulness stability. We also show that MCT2-mediated lactate uptake is necessary for maintaining tonic firing of orexinergic neurons and stabilizing wakefulness. Our findings provide both in vivo and in vitro evidence supporting the critical role of astrocyte-to-orexinergic neuron lactate shuttle in regulating proper sleep/wake stability— a crucial step for maintaining physiological functions and overall well-being.

Astrocytic metabolic control of orexinergic activity in the lateral hypothalamus regulates sleep and wake architecture

Nature Communications · 2024-07-16 · 24 citations

Neuronal activity undergoes significant changes during vigilance states, accompanied by an accommodation of energy demands. While the astrocyte-neuron lactate shuttle has shown that lactate is the primary energy substrate for sustaining neuronal activity in multiple brain regions, its role in regulating sleep/wake architecture is not fully understood. Here we investigated the involvement of astrocytic lactate supply in maintaining consolidated wakefulness by downregulating, in a cell-specific manner, the expression of monocarboxylate transporters (MCTs) in the lateral hypothalamus of transgenic mice. Our results demonstrate that reduced expression of MCT4 in astrocytes disrupts lactate supply to wake-promoting orexin neurons, impairing wakefulness stability. Additionally, we show that MCT2-mediated lactate uptake is necessary for maintaining tonic firing of orexin neurons and stabilizing wakefulness. Our findings provide both in vivo and in vitro evidence supporting the role of astrocyte-to-orexinergic neuron lactate shuttle in regulating proper sleep/wake stability.

3D bioengineered neural tissue generated from patient-derived iPSCs mimics time-dependent phenotypes and transcriptional features of Alzheimer’s disease

Molecular Psychiatry · 2023-06-26 · 19 citations

Neuronal activity drives pathway-specific depolarization of peripheral astrocyte processes

Nature Neuroscience · 2022-04-28 · 93 citations

3D bioengineered neural tissue generated from patient-derived iPSCs develops time-dependent phenotypes and transcriptional features of Alzheimer’s disease

bioRxiv (Cold Spring Harbor Laboratory) · 2022-07-22 · 2 citations

Abstract Background Current models to study Alzheimer’s disease (AD) include cell cultures and animal models. Human diseases, however, are often poorly reproduced in animal models. Developing techniques to differentiate human brain cells from induced pluripotent stem cells (iPSCs) provides a novel approach to studying AD. Three-dimensional (3D) cultures to model AD are represented by organoids, neurospheroids, and scaffold-based cultures. Some AD-related phenotypes have been identified across 3D models [1]. However, to our knowledge, none of these studies could recapitulate several AD-related hallmarks in one single model and establish a temporal relation among them. Furthermore, to date, the transcriptomic features of these 3D models have not been compared with those of human AD brains. These data are, in our opinion, key to understanding the pertinency of these models for studying AD-related pathomechanisms over time. Methods We developed a 3D bioengineered model of iPSC-derived neural tissue that combines a porous scaffold composed of silk fibroin protein with an intercalated collagen hydrogel to support the growth of neurons and glial cells into complex and functional networks. This biomaterial scaffold, designed to match the mechanical properties of brain tissue, can support 3D neural cultures for an extended time without necrosis, a fundamental requisite for aging studies. We have optimized our protocol by seeding neural precursor cells (NPCs) into these scaffolds. NPC-derived cultures were generated from iPSC lines obtained from two subjects carrying the familial AD (FAD) APP London mutation, two well-studied control lines, and an isogenic control. Cultures were analyzed at 2 and 4.5 months. Results An elevated Aβ42/40 ratio was detected in conditioned media from FAD cultures at both time points, as previously reported in 2D cultures derived from the same FAD lines. However, extracellular Aβ42 deposition and enhanced neuronal excitability were observed in FAD culture only at 4.5 months. The increased excitability of FAD cultures correlated with extracellular Aβ42 deposition but not with soluble Aβ42/40 ratio levels, as they were similar at both time points. These data suggest that extracellular Aβ deposition may trigger enhanced network activity. Notably, neuronal hyperexcitability has been described in AD patients early in the disease. Transcriptomic analysis revealed the deregulation of multiple gene sets in FAD samples. Notably, such alterations were similar to those observed in human AD brains in a large study that performed a co-expression meta-analysis of harmonized data from Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) across three independent cohorts. Conclusions Our 3D tissue model supports the differentiation of healthy iPSC-derived cultures in a porous silk-collagen composite sponge with an optically clear central region. This design facilitates nutrient delivery to meet the metabolic demand of long-term cultures. These data provide evidence that our bioengineered model from patient-derived FAD iPSCs develops time-dependent AD-related phenotypes and establishes a temporal relation among them. Furthermore, FAD iPSC-derived neuronal tissue recapitulates transcriptomic features of AD patients. Thus, our bioengineered neural tissue represents a unique tool to model AD-related pathomechanisms over time, with several advantages compared to the existing models.

Neuronal activity drives pathway-specific depolarization of astrocyte distal processes

bioRxiv (Cold Spring Harbor Laboratory) · 2021-07-04 · 5 citations

Abstract Astrocytes are glial cells that interact with neuronal synapses via their distal processes, where they remove glutamate and potassium (K + ) from the extracellular space following neuronal activity. Astrocyte clearance of both glutamate and K + is voltage-dependent, but astrocyte membrane potential (V m ) has been thought to be largely invariant. As a result, these voltage-dependencies have not been considered relevant to astrocyte function. Using genetically encoded voltage indicators enabling the measurement of V m at distal astrocyte processes (DAPs), we report large, rapid, focal, and pathway-specific depolarizations in DAPs during neuronal activity. These activity-dependent astrocyte depolarizations are driven by action potential-mediated presynaptic K + efflux and electrogenic glutamate transporters. We find that DAP depolarization inhibits astrocyte glutamate clearance during neuronal activity, enhancing neuronal activation by glutamate. This represents a novel class of sub-cellular astrocyte membrane dynamics and a new form of astrocyte-neuron interaction. One Sentence Summary Genetically encoded voltage imaging of astrocytes shows that presynaptic neuronal activity drives focal astrocyte depolarization, contributing to activity-dependent inhibition of glutamate uptake.