Coxsackievirus Adenovirus Receptor Loss Impairs Adult Neurogenesis, Synapse Content, and Hippocampus Plasticity

Abstract

Although we are beginning to understand the late stage of neurodegenerative diseases, the molecular defects associated with the initiation of impaired cognition are poorly characterized. Here, we demonstrate that in the adult brain, the coxsackievirus and adenovirus receptor (CAR) is located on neuron projections, at the presynapse in mature neurons, and on the soma of immature neurons in the hippocampus. In a proinflammatory or diseased environment, CAR is lost from immature neurons in the hippocampus. Strikingly, in hippocampi of patients at early stages of late-onset Alzheimer's disease (AD), CAR levels are significantly reduced. Similarly, in triple-transgenic AD mice, CAR levels in hippocampi are low and further reduced after systemic inflammation. Genetic deletion of CAR from the mouse brain triggers deficits in adult neurogenesis and synapse homeostasis that lead to impaired hippocampal plasticity and cognitive deficits. We propose that post-translational CAR loss of function contributes to cognitive defects in healthy and diseased-primed brains.

What is CAR doing in the middle of the adult neurogenic road?

“…We found that CAR levels significantly decrease here in a dose-dependent response. 7 We then asked if there was a connection in vivo by investigating if CAR levels in the brain are affected by systemic inflammation. Injection of lipopolysaccharides (LPS) into the peritoneal cavity did not affect global CAR levels.…”

“…14,[29][30][31][32] In hippocampal extracts from AD patients, we detected a significant decrease in CAR expression (on newborn neurons and in axons projecting from the entorhinal cortex, a region particularly affected in AD), suggesting that CAR is affected/involved in disorders where chronic inflammation, impaired adult neurogenesis, and synapse homeostasis are found. 7 Yet, it remains unclear as to why the genetic ablation of CAR expression (early in development) impacted female mice greater than male mice. The impact of CAR loss could be more readily understood in a "normal" environment (i.e., not in a transgenic mouse that is depleted in CAR during development).…”

“…not by microglia, macroglia or oligodendrocytes) in the adult mammalian brain parenchyma. 7 In the mouse brain, CAR staining is notable in the posterior corpus callosum, layers IV and V of the cerebral cortex, as well as cortex layer I, which contains primarily axons from other cortical areas and apical dendrites of local neurons. In the hippocampus, CAR staining is striking on the axons projecting from the entorhinal cortex, as well as in the stratum lucidum on the mossy fiber axons of newly generated DG neurons.…”

“…3,7 In the mouse DG, CAR covers the cell body of immature neurons, as determined by its location and overlap with PSA-NCAM (polysialylated neural cell adhesion molecule), and incorporation of a thymidine analog in the adult brain. 7 Of note for those using viral vectors (e.g. canine adenovirus type 2 or "CAV-2") that engage CAR as an attachment molecule, circumstantial evidence suggests that CAR is not expressed by all neuron subtypes.…”

“…[10][11][12] In contrast to the transcellular interaction in epithelial cells, we showed that when CAR is at the synapse of mature neurons, it is exclusively pre-but not post-synaptic. 7 However, not all neurons appear to be targeted by CAV-2 vectors. 8,9 For example, we have routinely had poor transgene expression when trying to transduce Purkinje cells in the mouse brain with CAV-2 vectors.…”