Abstract
Although the cause of progressive neurodegeneration is often unclear, neuronal death can occur through several mechanisms. In conditions such as Alzheimer’s or alcohol use disorder (AUD), Toll-like receptor (TLR) induction is observed with neurodegeneration. However, links between TLR activation and neurodegeneration are lacking. We report a role of apoptotic neuronal death in AUD through TLR7-mediated induction of death receptor signaling. In postmortem human cortex, a two-fold increase in apoptotic terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining in neurons was found in AUD versus controls. This occurred with the increased expression of TLR7 and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) death receptors. Binge ethanol treatment in C57BL/6 mice increased TLR7 and induced neuronal apoptosis in cortical regions that was blocked by TLR7 antagonism. Mechanistic studies in primary organotypic brain slice culture (OBSC) found that the inhibition of TLR7 and its endogenous ligand let-7b blocked ethanol-induced neuronal cell death. Both IMQ and ethanol induced the expression of TRAIL and its death receptor. In addition, TRAIL-neutralizing monoclonal antibodies blocked both imiquimod (IMQ) and ethanol induced neuronal death. These findings implicate TRAIL as a mediator of neuronal apoptosis downstream of TLR7 activation. TLR7 and neuronal apoptosis are implicated in other neurodegenerative diseases, including Alzheimer’s disease. Therefore, TRAIL may represent a therapeutic target to slow neurodegeneration in multiple diseases.
Highlights
IntroductionNeuronal cell death can occur through multiple mechanisms in settings of trauma, ischemia, or disease [1,2]
We have reported that TLR7 might contribute to neurodegeneration with alcohol abuse, with ethanol increasing the expression of TLR7 along with secretion of the endogenous agonist miRNA let-7b in primary ex vivo organotypic brain slice culture (OBSC) [10,13]
We used cadaveric sections from the New South Wales Brain Tissue Resource Centre (NSW-BTRC) [44] to determine if neuronal apoptosis contributes to neurodegeneration in alcohol use disorder (AUD)
Summary
Neuronal cell death can occur through multiple mechanisms in settings of trauma, ischemia, or disease [1,2]. In settings that involve progressive neurodegeneration such as alcohol use disorder (AUD), aging, or Alzheimer’s disease, the underlying cell death mechanisms can be more difficult to identify. Progressive pathologic neurodegeneration is often associated with a concomitant increased expression of neuroimmune genes and signs of microglial activation [3,4]. This can involve Toll-like receptor (TLR) activation through endogenous agonists known as damage-associated molecular pattern molecules (DAMPs) [4,5,6]. In diseases with a neurodegenerative component, concurrent increases in TLR signaling are usually observed [7,8,9]; the contribution of immune activation to ongoing neurodegeneration is often unclear
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