Senescent Schwann cells induced by aging and chronic denervation impair axonal regeneration following peripheral nerve injury.

Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype. We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c-Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c-Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.

Propositional density and apolipoprotein E genotype among persons at risk for familial Alzheimer's disease.

BACKGROUND/AIMS: A relationship between decreased propositional density (p-density) in young adulthood and future risk for Alzheimer's disease (AD) has been postulated, but multiple interpretations of the nature of this relationship are possible. This study explored the relationship between familial AD (FAD) mutation status, apolipoprotein E (APOE) genotype, and p-density. METHODS: Thirty-five non-demented persons at risk for FAD mutations were recruited. Subjects wrote brief biographical essays from which p-density, the ratio of the number of unique ideas to the number of words in the text, was calculated. mixed-effects regression models were used to examine the relationship of p-density and fad mutation status and apoe genotype. RESULTS: FAD mutation status was not significantly associated with p-density. However, results from both models indicated that the presence of the APOE ε4 allele was significantly associated with p-density (p < 0.0001), with APOE ε4 carriers having lower p-density than non-carriers. CONCLUSIONS: Our results are consistent with an influence of APOE status on p-density in young adulthood that is independent of the AD risk per se and suggest the previous finding of increased risk for the development of AD in persons with decreased p-density may be related to APOE genotype.

Effects of risk genes on BOLD activation in presymptomatic carriers of familial Alzheimer's disease mutations during a novelty encoding task.

Prior functional magnetic resonance imaging (fMRI) studies have found increased activity-related blood oxygen level-dependent (BOLD) signal in cognitively normal persons at genetic risk for Alzheimer's disease (AD). This has been interpreted as a compensatory response to incipient AD pathology. We studied the effects of fully penetrant familial Alzheimer's disease (FAD) mutations and apolipoprotein E (APOE) genotype on BOLD fMRI during a novelty encoding task in presymptomatic subjects. Twenty-three Mexican or Mexican-American persons at-risk for inheriting FAD mutations performed a block design novelty encoding task, and activation exhibited by FAD mutation carriers (MCs) was contrasted with that of noncarriers (NCs) and among APOE genotype groups. FAD MCs (n = 14) showed decreased BOLD activation in the anterior cingulate gyrus relative to 9 NCs. No increased activation was seen in MCs relative to NCs. Four APOE ε3/4 carriers demonstrated increased BOLD signal compared with 14 ε3/3 carriers in the occipital and perisylvian cortices bilaterally. There were no areas where ε3/3 carriers activated more than ε3/4 carriers. Our findings of increased fMRI activation associated with APOE genotype but not with FAD mutations suggest that APOE exerts an effect on the BOLD signal that is not readily explained as a compensatory phenomenon.