TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults

Abstract

Brain damage due to stroke or traumatic brain injury (TBI), both leading causes of serious long-term disability, often leads to the development of epilepsy. Patients who develop post-injury epilepsy tend to have poor functional outcomes. Emerging evidence highlights a potential role for blood-brain barrier (BBB) dysfunction in the development of post-injury epilepsy. However, common mechanisms underlying the pathological hyperexcitability are largely unknown. Here, we show that comparative transcriptome analyses predict remodeling of extracellular matrix (ECM) as a common response to different types of injuries. ECM-related transcriptional changes were induced by the serum protein albumin via TGFβ signaling in primary astrocytes. In accordance with transcriptional responses, we found persistent degradation of protective ECM structures called perineuronal nets (PNNs) around fast-spiking inhibitory interneurons, in a rat model of TBI as well as in brains of human epileptic patients. Exposure of a naïve brain to albumin was sufficient to induce the transcriptional and translational upregulation of molecules related to ECM remodeling and the persistent breakdown of PNNs around fast-spiking inhibitory interneurons, which was contingent on TGFβ signaling activation. Our findings provide insights on how albumin extravasation that occurs upon BBB dysfunction in various brain injuries can predispose neural circuitry to the development of chronic inhibition deficits.

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

“…Activated astrocytes further downregulate inward‐rectifier potassium channel and glutamate transporter, resulting in reduced potassium and glutamate buffering, leading to neuronal hyperexcitability . In addition, astrocytic‐mediated alterations in the extracellular matrix, excitatory synaptogenesis, and pathological plasticity contribute to the ongoing process of epileptogenesis …”

Blood-brain barrier dysfunction in aging induces hyper-activation of TGF-beta signaling and chronic yet reversible neural dysfunction

“…Albumin endocytosis into astrocytes is mediated by binding to the TGFβ receptor II (TGFβR) subunit, which in turn activates the TGFβRI ALK5 (22,28) to induce phosphorylation of Smad2 (pSmad2) and carry out signal transduction of the ALK5-TGFβ signaling cascade. Further, this activation also increases the production of TGFβ1 in astrocytes (Weissberg et al, 2015) and activation of latent TGFβ1 protein from extra-cellular matrix (26), yielding an increase in the canonical ligand of TGFβR and therefore amplification of the TGFβ cascade. Hence, we next investigated the relationship between albumin uptake and TGFβ signaling in the aged mouse brain by quantifying immunolabeled phosphorylated Smad2 protein (pSmad2).…”

“…Based on the finding that BBB dysfunction and TGFβ signaling causes hyperexcitability after head injury (22,24,(26)(27)(28)39), we hypothesized that similar hyperexcitability may be triggered by BBB decline and contribute to cognitive impairment in aging mice. Indeed, hippocampal hyperexcitability is an early biomarker of mild cognitive impairment in humans that precedes progression to AD (42,43), and is also an early marker of disease progression in rodent AD models (44,45).…”

“…2A; Table S1). We first established normal levels of brain permeability based on permeability values in healthy, young patients (age [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], setting an upper value for "normal permeability" at the 95 th percentile (i.e. 95% of brain voxels in the averaged healthy young brain were below this value).…”

“…In both cases, astrocytes act as the primary responders that detect the blood-borne ligands and transduce TGFβ signaling (21)(22)(23). In turn, activated astrocytes release inflammatory cytokines and more TGFβ1 (22,24,25), form glial scars (21), and remodel neural circuits to cause hyperexcitability and dysfunction (22,24,(26)(27)(28). These studies point to the TGFβ signaling pathway as a candidate mechanism that could play a role in pathological outcomes following BBB breakdown in aging.…”