SUMMARY Predisposition to sporadic Alzheimer’s disease (SAD) involves interactions between a person’s unique combination of genetic variants and the environment. The molecular effect of these variants may be subtle and difficult to analyze with standard in vitro or in vivo models. Here we used hIPSCs to examine genetic variation in the SORL1 gene and possible contributions to SAD-related phenotypes in human neurons. We found that human neurons carrying SORL1 variants associated with an increased SAD risk show a reduced response to treatment with BDNF, at the level of both SORL1 expression and APP processing. shRNA knockdown of SORL1 demonstrates that the differences in BDNF-induced APP processing between genotypes are dependent on SORL1 expression. We propose that the variation in SORL1 expression induction by BDNF is modulated by common genetic variants and can explain how genetic variation in this one locus can contribute to an individual’s risk of developing SAD.

Presenilin 1 (PS1) is the catalytic core of γ-secretase, which cleaves type-1 transmembrane proteins including the amyloid precursor protein (APP). PS1 also has γ-secretase independent functions and dominant PS1 missense mutations are the most common cause of familial Alzheimer’s disease (FAD). Whether PS1 FAD mutations are gain or loss-of-function remains controversial, primarily because most studies have relied on overexpression in mouse and/or non-neuronal systems. We used isogenic euploid human iPSC lines to generate and study an allelic series of PS1 mutations including heterozygous null mutations and homozygous and heterozygous FAD PS1 mutations. Rigorous analysis of this allelic series in differentiated, purified neurons allowed us to resolve this controversy and to conclude that FAD PS1 mutations, expressed at normal levels in the appropriate cell-type, impair γ-secretase activity, but do not disrupt γ-secretase independent functions of PS1. Thus, FAD PS1 mutations do not act as simple loss of PS1 function, but instead dominantly gain an activity toxic to some, but not all PS1 functions.

Background Mild traumatic brain injury (mTBI; cerebral concussion) results in cognitive and emotional dysfunction. These injuries are a significant risk factor for the development of anxiety disorders including post-traumatic stress disorder (PTSD). However, because physically traumatic events typically occur in a highly emotional context, it is unknown whether TBI itself is a cause of augmented fear and anxiety. Methods Rats were trained with one of five fear conditioning procedures (N = 105) two days after concussive brain trauma. Fear learning was assessed over subsequent days and chronic changes in fear learning and memory circuitry were assessed by measuring NMDA receptor subunits and GAD-67 protein levels in the hippocampus and basolateral amygdala complex (BLA). Results Injured rats exhibited an overall increase in fear conditioning regardless of whether fear was retrieved via discrete or contextual-spatial stimuli. Moreover, injured rats appeared to over generalize learned fear to both conditioned and novel stimuli. Although no gross histopathology was evident, injury resulted in a significant up-regulation of excitatory NMDA receptors in the BLA. There was a trend toward decreased GABA related inhibition (GAD-67) in the BLA and hippocampus. Conclusions These results suggest that mTBI predisposes the brain toward heightened fear learning during stressful post-injury events and provides a potential molecular mechanism by which this occurs. Furthermore, these data represent a novel rodent model that can help advance the neurobiological and therapeutic understanding of the co-morbidity of PTSD and TBI.