The synaptic changes underlying the onset of cognitive impairment in Alzheimer’s disease (AD) are poorly understood. In contrast to the well documented inhibition of long-term potentiation (LTP) in CA3-CA1 synapses by acute Aβ application in adult neurons from rodents, young amyloid precursor protein (APP) transgenic mouse models often, surprisingly, show normal LTP. This suggests that there may be important differences between mature-onset and developmental-onset APP expression/ Aβ accumulation and the ensuing synaptic and behavioural phenotype. Here, in agreement with previous studies, we observed that developmental expression of APP Sw,Ind (3–4 month old mice from line 102, PLoS Med 2:e355, 2005), resulted in reduced basal synaptic transmission in CA3-CA1 synapses, normal LTP, impaired spatial working memory, but normal spatial reference memory. To analyse early Aβ-mediated synaptic dysfunction and cognitive impairment in a more mature brain, we used controllable mature-onset APP Sw,Ind expression in line 102 mice. Within 3 weeks of mature-onset APP Sw,Ind expression and Aβ accumulation, we detected the first synaptic dysfunction: an impairment of LTP in hippocampal CA3-CA1 synapses. Cognitively, at this time point, we observed a deficit in short-term memory. A reduction in basal synaptic strength and deficit in long-term associative spatial memory were only evident following 12 weeks of APP Sw,Ind expression. Importantly, the plasticity impairment observed after 3 weeks of mature-onset APP expression is reversible. Together, these findings demonstrate important differences between developmental and mature-onset APP expression. Further research targeted at this early stage of synaptic dysfunction could help identify mechanisms to treat cognitive impairment in mild cognitive impairment (MCI) and early AD.

Macrophages are abundant in the cochlea; however, their role in hearing loss is not well understood. Insults to the cochlea, such as noise or insertion of a cochlear implant, cause an inflammatory response, which includes activation of tissue‐resident macrophages. Activation is characterized by changes in macrophage morphology, mediator expression, and distribution. Evidence from other organs shows activated macrophages can become primed, whereby subsequent insults cause an elevated inflammatory response. Primed macrophages in brain pathologies respond to circulating inflammatory mediators by disproportionate synthesis of inflammatory mediators. This signaling occurs behind an intact blood–brain barrier, similar to the blood‐labyrinth barrier in the cochlea. Local tissue damage can occur as the result of mediator release by activated macrophages. Damage is typically localized; however, if it is to structures with limited ability to repair, such as neurons or hair cells within the cochlea, it is feasible that this contributes to the progressive loss of function seen in hearing loss. We propose that macrophages in the cochlea link risk factors and hearing loss. Injury to the cochlea causes local macrophage activation that typically resolves. However, in susceptible individuals, some macrophages enter a primed state. Once primed, these macrophages can be further activated, as a consequence of circulating inflammatory molecules associated with common co‐morbidities. Hypothetically, this would lead to further cochlear damage and loss of hearing. We review the evidence for the role of tissue‐resident macrophages in the cochlea and propose that cochlear macrophages contribute to the trajectory of hearing loss and warrant further study.

Objective: The reasons for soft failure after cochlear implantation require investigation. This study proposes a method to study and characterize the tissue response to the array in a case of soft failure in a person undergoing reimplantation. Case: The woman in her 50s, with an underlying autoimmune condition, received a cochlear implant using hearing preservation technique after developing profound hearing loss more than 2 kHz with a moderate loss of less than 500 Hz over a 10-year period. The case was identified as a soft failure due to deteriorating performance, discomfort, and migration over the 10 months after implantation. Impedance telemetry, speech perception measures, and audiometric thresholds are described. At explantation there was evidence of fibrosis. Intervention(s): To use histology and immunohistochemistry to determine the cellular response of the tissue associated with the electrode array at time of explantation. Main Outcome Measure(s): Identification of the cell types, regional variations, and inflammatory marker expression in the fibrotic tissue associated with the array. Results: Neutrophils and eosinophils were identified, along with a variable pattern of collagen deposition. CD68 and CD163-positive macrophages and T cells were variably distributed through the tissue and interleukin-1 beta and vascular endothelial growth factor receptor-2 expression was identified. Conclusions: The expression profile is evidence of active inflammation in the tissue despite the time since implantation. This study is the first to characterize the tissue response to the array in a person undergoing reimplantation, and who can be followed to determine the individual response to arrays. It establishes that the investigation of explanted devices after soft-failure is feasible.

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