The Aβ peptide aggregates into amyloid plaques at presymptomatic stages of Alzheimer's disease, but the temporal relationship between plaque formation and neuronal dysfunction is poorly understood. Here, we demonstrate that the connectivity of the peripheral olfactory neural circuit is perturbed in mice overexpressing human APPsw (Swedish mutation) prior to the onset of plaques. Expression of hAPPsw exclusively in olfactory sensory neurons (OSNs) also perturbs connectivity with associated reductions in odor-evoked gene expression and olfactory acuity. By contrast, OSN axons project correctly in mice overexpressing wild type human APP throughout the brain and in mice overexpressing human APPmv, a missense mutation that reduces Aβ production, exclusively in OSNs. Furthermore, expression of Aβ40 or Aβ42 solely in the olfactory epithelium disrupts OSN axon targeting. Our data indicate that altering the structural connectivity and function of highly plastic neural circuits is one of the pleiotropic actions of soluble human Aβ.

Triggers of innate immune signaling in the CNS of patients with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) remain elusive. We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. The presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neuronal class induced IFN-I and death in connected neurons non–cell-autonomously. Our findings establish that genomically encoded cdsRNAs trigger sterile, viral-mimetic IFN-I induction and propagated death within neural circuits and may drive neuroinflammation and neurodegeneration in patients with ALS/FTD.

While diminishing nephrology fellow recruitment is a known issue, more work is needed to evaluate possible interventions to reverse this trend. We designed and implemented a curriculum to increase exposure to ambulatory nephrology among internal medicine interns. The curriculum focused on key aspects of outpatient nephrology practice including supervised clinic visits, formal themed didactic content, and an online interactive forum with assigned evidence-based readings and small-group responses to relevant cases. We obtained post-course surveys from all participating interns. Of the 43 interns who took part in the first year of the ambulatory nephrology curriculum, 100% of interns reported a positive didactic experience and 91% reported a positive interactive online experience. 77% reported an improvement in their familiarity with clinical nephrology practice (median 2 point increase in familiarity score on a 7-point scale, p<0.001 by signed-rank testing). Qualitative feedback included praise for the high yield topics covered by the lectures and energizing teachers. In conclusion, we successfully implemented an ambulatory nephrology curriculum using a framework that integrated formal didactics, interactive online learning, and key clinical components of outpatient nephrology care. Future investigation will evaluate if early implementation of this curriculum is associated with increased pursuit of nephrology as a career.