Teneurins (TENs) are cell-surface adhesion proteins with critical roles in tissue development and axon guidance. Here, we report the 3.1-Å cryoelectron microscopy structure of the human TEN2 extracellular region (ECR), revealing a striking similarity to bacterial Tc-toxins. The ECR includes a large β barrel that partially encapsulates a C-terminal domain, which emerges to the solvent through an opening in the mid-barrel region. An immunoglobulin (Ig)-like domain seals the bottom of the barrel while a β propeller is attached in a perpendicular orientation. We further show that an alternatively spliced region within the β propeller acts as a switch to regulate trans-cellular adhesion of TEN2 to latrophilin (LPHN), a transmembrane receptor known to mediate critical functions in the central nervous system. One splice variant activates trans-cellular signaling in a LPHN-dependent manner, whereas the other induces inhibitory postsynaptic differentiation. These results highlight the unusual structural organization of TENs giving rise to their multifarious functions.

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A central question in the field of aging research is to identify the cellular and molecular basis of neuroresilience. One potential candidate is the small GTPase, Rab10. Here we used Rab10+/-mice to investigate the molecular mechanisms underlying Rab10-mediated neuroresilience. Brain expression analysis of 880 genes involved in neurodegeneration showed that Rab10+/-mice have increased activation of pathways associated with neuronal metabolism, structural integrity, neurotransmission, and neuroplasticity compared to their Rab10+/+littermates. Lower activation was observed for pathways involved in neuroinflammation and aging. We identified and validated several differentially expressed genes (DEGs) including Stx2, Stx1b, Vegfa, Lrrc25 (downregulated); and Prkaa2, Syt4 and Grin2d (upregulated). Behavioral testing showed that Rab10+/-mice perform better in a hippocampal-dependent spatial task (object in place test), while their performance in a classical conditioning task (trace eyeblink conditioning, TECC) was significantly impaired. Therefore, our findings indicate that Rab10 differentially controls the brain circuitry of hippocampal-dependent spatial memory and higher-order behavior that requires intact cortex-hippocampal circuitry. Transcriptome and biochemical characterization of these mice suggest that glutamate ionotropic receptor NMDA type subunit 2D (GRIN2D or GluN2D) is affected by Rab10 signaling. Further work is needed to evaluate whether GRIN2D mediates the behavioral phenotypes of the Rab10+/-mice. We conclude that Rab10+/-mice described here can be a valuable tool to study the mechanisms of resilience in Alzheimer’s disease model mice and to identify novel therapeutical targets to prevent cognitive decline associated with normal and pathological aging.SIGNIFICANCE STATEMENTAlzheimer’s disease (AD) is characterized by a widespread collapse of neuronal circuits that precedes amyloid plaque deposition and tau pathology. Yet, 30-50% of older individuals, who harbor the anatomical and molecular features of AD, preserve their cognitive abilities, and do not show AD symptoms in their lifetime. It has been suggested that the Rab10 protein is among the mediators of “cognitive resilience” against AD. The focus of this work was to characterize Rab10+/-mice behaviorally and molecularly, and to identify downstream targets of Rab10-dependent neuroresilience. The Rab10+/-mice described here can be used to study cellular and molecular mechanisms of Rab10-dependent resilience in mouse models of AD.